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Entry
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- %222100 - TYPE 1 DIABETES MELLITUS; T1D
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- OMIM
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<span class="h4">%222100</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="/clinicalSynopsis/222100"><strong>Clinical Synopsis</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#otherFeatures">Other Features</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#history">History</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=TYPE 1 DIABETES MELLITUS" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=222100[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div style="display: table-cell;">Animal Models</div>
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<div><a href="http://www.informatics.jax.org/disease/222100" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://omia.org/results?search_type=advanced&omia_id=000279,000283" class="mim-tip-hint" title="OMIA" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OMIA', 'domain': 'omia.angis.org.au'})">OMIA</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:9744" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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</a>
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:222100" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 46635009<br />
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<strong>ICD10CM:</strong> E10<br />
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<strong>DO:</strong> 9744<br />
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">ICD+</a>
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<div>
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Phenotype description or locus, molecular basis unknown">
|
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<span class="text-danger"><strong>%</strong></span>
|
|
222100
|
|
</span>
|
|
</span>
|
|
</div>
|
|
</div>
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|
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|
<div>
|
|
<a id="preferredTitle" class="mim-anchor"></a>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
TYPE 1 DIABETES MELLITUS; T1D
|
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</span>
|
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</h3>
|
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</div>
|
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<div>
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<br />
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</div>
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<div>
|
|
<a id="alternativeTitles" class="mim-anchor"></a>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
DIABETES MELLITUS, INSULIN-DEPENDENT; IDDM<br />
|
|
JUVENILE-ONSET DIABETES; JOD
|
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</span>
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="includedTitles" class="mim-anchor"></a>
|
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<div>
|
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<p>
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|
<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
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</div>
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<div>
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<span class="h3 mim-font">
|
|
TYPE 1 DIABETES MELLITUS 1, INCLUDED; T1D1, INCLUDED
|
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</span>
|
|
</div>
|
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<div>
|
|
<span class="h4 mim-font">
|
|
|
|
DIABETES MELLITUS, INSULIN-DEPENDENT, 1, INCLUDED; IDDM1, INCLUDED<br />
|
|
INSULIN-DEPENDENT DIABETES MELLITUS 1, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/6/251?start=-3&limit=10&highlight=251">6p21.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr6:30500001-36600000&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">6:30,500,001-36,600,000</a> </span>
|
|
</em>
|
|
</strong>
|
|
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/6/251?start=-3&limit=10&highlight=251">
|
|
6p21.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Diabetes mellitus, insulin-dependent-1}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/222100"> 222100 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="2 - The disorder was placed on the map by statistical methods">2</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/222100" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/222100" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/222100" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
|
|
|
|
|
|
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> Endocrine </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Diabetes mellitus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/73211009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">73211009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E08-E13" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E08-E13</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">250</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011849&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011849</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000819" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000819</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000819" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000819</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> Metabolic </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Ketoacidosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/56051008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">56051008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0220982&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0220982</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001993" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001993</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001993" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001993</a>]</span><br /> - Abnormally increased gluconeogenesis<br /> - Insufficient glucose disposal<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> Immunology </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Pancreatic autoimmunity<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> GI </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Polydipsia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/17173007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">17173007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/139104001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">139104001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R63.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R63.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085602&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085602</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001959" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001959</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001959" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001959</a>]</span><br /> - Polyphagia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/58424009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">58424009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/267023007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">267023007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/72405004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">72405004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R63.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R63.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.6</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020505&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020505</a>, <a href="https://bioportal.bioontology.org/search?q=C0232461&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0232461</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002591" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002591</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002591" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002591</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> GU </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Polyuria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/56574000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">56574000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/28442001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">28442001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/718402002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">718402002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R35" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R35</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R35.89" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R35.89</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/788.42" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">788.42</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0032617&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0032617</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000103" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000103</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000103" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000103</a>]</span><br /> - Hyperglycemia-induced osmotic diuresis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806278&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806278</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> Lab </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
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<p>Type 1 diabetes mellitus (T1D), also designated insulin-dependent diabetes mellitus (IDDM), is a disorder of glucose homeostasis characterized by susceptibility to ketoacidosis in the absence of insulin therapy. It is a genetically heterogeneous autoimmune disease affecting about 0.3% of Caucasian populations (<a href="#138" class="mim-tip-reference" title="Todd, J. A. <strong>Genetic control of autoimmunity in type 1 diabetes.</strong> Immun. Today 11: 122-129, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2187469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2187469</a>] [<a href="https://doi.org/10.1016/0167-5699(90)90049-f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2187469">Todd, 1990</a>). Genetic studies of T1D have focused on the identification of loci associated with increased susceptibility to this multifactorial phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2187469" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The classic phenotype of diabetes mellitus is polydipsia, polyphagia, and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.</p>
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<p>The term diabetes mellitus is not precisely defined and the lack of a consensus on diagnostic criteria has made its genetic analysis difficult. Diabetes mellitus is classified clinically into 2 major forms of the primary illness, insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM; <a href="/entry/125853">125853</a>), and secondary forms related to gestation or medical disorders.</p><p>Appearance of the IDDM phenotype is thought to require a predisposing genetic background and interaction with other environmental factors. <a href="#111" class="mim-tip-reference" title="Rotter, J. I., Rimoin, D. L. <strong>Heterogeneity in diabetes mellitus--update, 1978.</strong> Diabetes 27: 599-608, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/348539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">348539</a>] [<a href="https://doi.org/10.2337/diab.27.5.599" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="348539">Rotter and Rimoin (1978)</a> hypothesized that there are at least 2 forms of IDDM: a B8 (DR3)-associated form characterized by pancreatic autoimmunity, and a B15-associated form characterized by antibody response to exogenous insulin. Interestingly, the DR3 and DR4 alleles seem to have a synergistic effect on the predisposition to IDDM based on the greatly increased risk observed in persons having both the B8 and B15 antigens (<a href="#129" class="mim-tip-reference" title="Svejgaard, A., Ryder, L. P. <strong>Associations between HLA and disease. In: Dausset, J.; Svejgaard, A.: HLA and Disease.</strong> Copenhagen: Munksgaard (pub.) 1977. Pp. 46-71."None>Svejgaard and Ryder, 1977</a>). <a href="#112" class="mim-tip-reference" title="Rotter, J. I., Rimoin, D. L. <strong>Diabetes mellitus: the search for genetic markers.</strong> Diabetes Care 2: 215-216, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/293258/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">293258</a>] [<a href="https://doi.org/10.2337/diacare.2.2.215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="293258">Rotter and Rimoin (1979)</a> hypothesized a combined form. <a href="#139" class="mim-tip-reference" title="Tolins, J. P., Raij, L. <strong>Genetic factors and susceptibility to diabetic nephropathy. (Letter)</strong> New Eng. J. Med. 319: 180-181, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3386702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3386702</a>] [<a href="https://doi.org/10.1056/NEJM198807213190316" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3386702">Tolins and Raij (1988)</a> cited clinical and experimental evidence to support the idea that those IDDM patients in whom diabetic nephropathy (see <a href="/entry/603933">603933</a>) eventually develops may have a genetic predisposition to essential hypertension. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3386702+348539+293258" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#47" class="mim-tip-reference" title="Gambelunghe, G., Ghaderi, M., Tortoioli, C., Falorni, A., Santeusanio, F., Brunetti, P., Sanjeevi, C. B., Falorni, A. on behalf of the Umbria Type 1 Diabetes Registry. <strong>Two distinct MICA gene markers discriminate major autoimmune diabetes types.</strong> J. Clin. Endocr. Metab. 86: 3754-3760, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11502807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11502807</a>] [<a href="https://doi.org/10.1210/jcem.86.8.7769" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11502807">Gambelunghe et al. (2001)</a> noted heterogeneity of the clinical and immunologic features of IDDM in relation to age at clinical onset. Childhood IDDM is characterized by an abrupt onset and ketosis and is associated with HLA-DRB1*04-DQA1*0301-DQB1*0302 and a high frequency of insulin and IA-2 autoantibodies. On the other hand, the so-called latent autoimmune diabetes of the adult (LADA) is a slowly progressive form of adult-onset autoimmune diabetes that is noninsulin-dependent at the time of clinical diagnosis and is characterized by the presence of glutamic acid decarboxylase-65 (GAD65: <a href="/entry/138275">138275</a>) autoantibodies and/or islet cell antibodies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11502807" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#87" class="mim-tip-reference" title="Nepom, B. S., Schwarz, D., Palmer, J. P., Nepom, G. T. <strong>Transcomplementation of HLA genes in IDDM: HLA-DQ alpha- and beta-chains produce hybrid molecules in DR3/4 heterozygotes.</strong> Diabetes 36: 114-117, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3491769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3491769</a>] [<a href="https://doi.org/10.2337/diab.36.1.114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3491769">Nepom et al. (1987)</a> studied the mechanism of the exaggerated susceptibility to IDDM in DR3/DR4 heterozygotes, and concluded that its basis is the formation of hybrid molecules of the closely linked DQ-alpha (HLA-DQA1; <a href="/entry/146880">146880</a>) and -beta (HLA-DQB1; <a href="/entry/604305">604305</a>) chains. The DR-alpha molecules are not polymorphic, and mixed DR alpha-beta dimers would not result in novel HLA molecules. On the other hand, both the alpha and beta chains of DQ are polymorphic, and a DQ alpha-beta dimer composed of transcomplementing chains would be unique to a heterozygous individual and not expressed in either parent. In the mouse, such transcomplementation has been demonstrated structurally, and epitopes newly formed in the resulting hybrid molecules allow for an altered functional immune response different from that of either parent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3491769" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The human MHC class II molecule encoded by DQA1*0102/DQB1*0602 (termed DQ0602) confers strong susceptibility to narcolepsy (<a href="/entry/161400">161400</a>) but dominant protection against type 1 diabetes. To elucidate the molecular features underlying these contrasting genetic properties, <a href="#119" class="mim-tip-reference" title="Siebold, C., Hansen, B. E., Wyer, J. R., Harlos, K., Esnouf, R. E., Svejgaard, A., Bell, J. I., Strominger, J. L., Jones, E. Y., Fugger, L. <strong>Crystal structure of HLA-DQ0602 that protects against type 1 diabetes and confers strong susceptibility to narcolepsy.</strong> Proc. Nat. Acad. Sci. 101: 1999-2004, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14769912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14769912</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14769912[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0308458100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14769912">Siebold et al. (2004)</a> determined the crystal structure of the DQ0602 molecule at 1.8-angstrom resolution. Structural comparisons to homologous DQ molecules with differential disease associations highlighted a previously unrecognized interplay between the volume of the P6 pocket and the specificity of the P9 pocket, which implies that presentation of the expanded peptide repertoire is critical for dominant protection against type 1 diabetes. In narcolepsy, the volume of the P4 pocket appears central to the susceptibility, suggesting that the presentation of a specific peptide population plays a major role. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14769912" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Hyperglycemia, the basic metabolic abnormality in IDDM, is caused by abnormally increased gluconeogenesis and insufficient glucose disposal. Ketosis results from the accumulation of free fatty acids and their oxidation.</p><p><a href="#78" class="mim-tip-reference" title="McCorry, D., Nicolson, A., Smith, D., Marson, A., Feltbower, R. G., Chadwick, D. W. <strong>An association between type 1 diabetes and idiopathic generalized epilepsy.</strong> Ann. Neurol. 59: 204-206, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16374819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16374819</a>] [<a href="https://doi.org/10.1002/ana.20727" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16374819">McCorry et al. (2006)</a> found an association between IDDM and idiopathic generalized epilepsy (EIG; <a href="/entry/600669">600669</a>) in a population-based survey in the U.K. Among 518 EIG patients aged 15 to 30 years, 7 also had IDDM. In contrast, there were 465 IDDM patients among an age-matched cohort of 150,000 individuals. The findings suggested that the prevalence of IDDM is increased in patients with EIG (odds ratio of 4.4). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16374819" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Patients with type 1 diabetes have diminished responses following T-cell activation. By immunoblot analysis, <a href="#90" class="mim-tip-reference" title="Nervi, S., Atlan-Gepner, C., Kahn-Perles, B., Lecine, P., Vialettes, B., Imbert, J., Naquet, P. <strong>Specific deficiency of p56(lck) expression in T lymphocytes from type 1 diabetic patients.</strong> J. Immun. 165: 5874-5883, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11067948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11067948</a>] [<a href="https://doi.org/10.4049/jimmunol.165.10.5874" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11067948">Nervi et al. (2000)</a> found reduced levels of phosphorylated CD3Z (<a href="/entry/186780">186780</a>) in IDDM1 patients after T-cell stimulation. Immunoblot, immunoprecipitation, and densitometric analyses revealed significantly reduced LCK expression in unstimulated peripheral blood cells of IDDM1 patients compared to controls. The reduced LCK expression correlated with a lower proliferative response. Very low LCK expression may also correlate with the HLA-DQB1*0201/0302 (see <a href="/entry/604305">604305</a>) genotype. Confocal microscopy demonstrated normal plasma membrane expression of LCK in patients and controls. Downstream signal transducing molecules were not affected in these patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11067948" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#63" class="mim-tip-reference" title="Kent, S. C., Chen, Y., Bregoli, L., Clemmings, S. M., Kenyon, N. S., Ricordi, C., Hering, B. J., Hafler, D. A. <strong>Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope.</strong> Nature 435: 224-228, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15889096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15889096</a>] [<a href="https://doi.org/10.1038/nature03625" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15889096">Kent et al. (2005)</a> examined T cells from pancreatic draining lymph nodes, the site of islet cell-specific self-antigen presentation. They cloned single T cells in a nonbiased manner from pancreatic draining lymph nodes of patients with type 1 diabetes and from nondiabetic controls. A high degree of T-cell clonal expansion was observed in pancreatic lymph nodes from long-term diabetic patients but not from controls. The oligoclonally expanded T cells from diabetic patients with DR4, a susceptibility allele for type 1 diabetes, recognized the insulin A 1-15 epitope restricted by DR4. <a href="#63" class="mim-tip-reference" title="Kent, S. C., Chen, Y., Bregoli, L., Clemmings, S. M., Kenyon, N. S., Ricordi, C., Hering, B. J., Hafler, D. A. <strong>Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope.</strong> Nature 435: 224-228, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15889096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15889096</a>] [<a href="https://doi.org/10.1038/nature03625" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15889096">Kent et al. (2005)</a> concluded that their results identified insulin-reactive, clonally expanded T cells from the site of autoinflammatory drainage in long-term type 1 diabetics, indicating that insulin may indeed be the target antigen causing autoimmune diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15889096" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#97" class="mim-tip-reference" title="Porter, J. R., Barrett, T. G. <strong>Monogenic syndromes of abnormal glucose homeostasis: clinical review and relevance to the understanding of the pathology of insulin resistance and beta cell failure.</strong> J. Med. Genet. 42: 893-902, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15772126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15772126</a>] [<a href="https://doi.org/10.1136/jmg.2005.030791" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15772126">Porter and Barrett (2005)</a> reviewed monogenic syndromes of abnormal glucose homeostasis, focusing on 3 mechanisms: insulin resistance, insulin secretion defects, and beta-cell apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15772126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#123" class="mim-tip-reference" title="Stechova, K., Halbhuber, Z., Hubackova, M., Kayserova, J., Petruzelkova, L., Vcelakova, J., Kolouskova, S., Ulmannova, T., Faresjo, M., Neuwirth, A., Spisek, R., Sediva, A., Filipp, D., Sumnik, Z. <strong>Case report: type 1 diabetes in monozygotic quadruplets.</strong> Europ. J. Hum. Genet. 20: 457-462, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22108602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22108602</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22108602[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2011.212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22108602">Stechova et al. (2012)</a> reported a family with naturally conceived monozygotic female quadruplets, in which type 1 diabetes was diagnosed in 2 of the quadruplets simultaneously and a third quadruplet was diagnosed as pre-diabetic. All 4 quadruplets were positive for anti-islet cell autoantibodies to GAD65 (<a href="/entry/138275">138275</a>) and to IA-2 (<a href="/entry/601773">601773</a>), indicating an ongoing anti-islet autoimmunity in the nondiabetic quadruplets. Serologic examination confirmed that all the quadruplets and their father had recently undergone an enteroviral infection of the EV68-81 serotype. Immunocompetent cells from all family members were characterized by gene expression arrays, immune-cell enumerations, and cytokine-production assays. The microarray data provided evidence that the viral infection and IL27 (<a href="/entry/608273">608273</a>) and IL9 (<a href="/entry/146931">146931</a>) cytokine signaling contributed to the onset of T1D in 2 of the quadruplets. <a href="#123" class="mim-tip-reference" title="Stechova, K., Halbhuber, Z., Hubackova, M., Kayserova, J., Petruzelkova, L., Vcelakova, J., Kolouskova, S., Ulmannova, T., Faresjo, M., Neuwirth, A., Spisek, R., Sediva, A., Filipp, D., Sumnik, Z. <strong>Case report: type 1 diabetes in monozygotic quadruplets.</strong> Europ. J. Hum. Genet. 20: 457-462, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22108602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22108602</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22108602[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2011.212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22108602">Stechova et al. (2012)</a> stated that the propensity of stimulated immunocompetent cells from nondiabetic members of the family to secrete high levels of IFN-alpha (IFNA1; <a href="/entry/147660">147660</a>) further corroborated their conclusion. They observed that the number of T-regulatory cells as well as plasmacytoid and/or myeloid dendritic cells was diminished in all family members. <a href="#123" class="mim-tip-reference" title="Stechova, K., Halbhuber, Z., Hubackova, M., Kayserova, J., Petruzelkova, L., Vcelakova, J., Kolouskova, S., Ulmannova, T., Faresjo, M., Neuwirth, A., Spisek, R., Sediva, A., Filipp, D., Sumnik, Z. <strong>Case report: type 1 diabetes in monozygotic quadruplets.</strong> Europ. J. Hum. Genet. 20: 457-462, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22108602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22108602</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22108602[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2011.212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22108602">Stechova et al. (2012)</a> concluded that this family supported the so-called 'fertile-field' hypothesis proposing that genetic predisposition to anti-islet autoimmunity, if 'fertilized' and precipitated by a viral infection, results in full-blown type 1 diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22108602" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>IDDM exhibits 30 to 50% concordance in monozygotic twins, suggesting that the disorder is dependent on environmental factors as well as genes. The average risk to sibs is 6% (<a href="#138" class="mim-tip-reference" title="Todd, J. A. <strong>Genetic control of autoimmunity in type 1 diabetes.</strong> Immun. Today 11: 122-129, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2187469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2187469</a>] [<a href="https://doi.org/10.1016/0167-5699(90)90049-f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2187469">Todd, 1990</a>). Recessive, dominant, and multifactorial hypotheses have been advanced, as well as 'susceptibility' hypotheses (<a href="#113" class="mim-tip-reference" title="Rotter, J. I. <strong>The modes of inheritance of insulin-dependent diabetes mellitus, or the genetics of IDDM, no longer a nightmare but still a headache.</strong> Am. J. Hum. Genet. 33: 835-851, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7034532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7034532</a>]" pmid="7034532">Rotter, 1981</a>). Genetic and environmental influences in IDDM were reviewed by <a href="#29" class="mim-tip-reference" title="Craighead, J. E. <strong>Current views on the etiology of insulin-dependent diabetes mellitus.</strong> New Eng. J. Med. 299: 1439-1445, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/362209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">362209</a>] [<a href="https://doi.org/10.1056/NEJM197812282992605" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="362209">Craighead (1978)</a>. Usually in genetic disease the most severe form of a disorder shows the clearest genetic basis. It is therefore surprising to find that the genetics of IDDM is less clear than that of NIDDM. Concordance in NIDDM was 100% for identical twins in which the index case had onset of diabetes after age 45 years, and nearly half had a diabetic parent, while discordance was found in half the pairs with earlier onset, few of whom had a family history of diabetes (<a href="#130" class="mim-tip-reference" title="Tattersall, R. B., Pyke, D. A. <strong>Diabetes in identical twins.</strong> Lancet 300: 1120-1125, 1972. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4117207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4117207</a>] [<a href="https://doi.org/10.1016/s0140-6736(72)92720-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4117207">Tattersall and Pyke, 1972</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=362209+4117207+2187469+7034532" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#91" class="mim-tip-reference" title="Nilsson, S. E. <strong>On the heredity of diabetes mellitus and its interrelationship with some other diseases.</strong> Acta Genet. Statist. Med. 14: 97-124, 1964.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14215758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14215758</a>] [<a href="https://doi.org/10.1159/000151837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14215758">Nilsson (1964)</a> commented on the difficulties of distinguishing dominant and recessive inheritance when gene frequency is high. He considered autosomal recessive inheritance of IDDM to be most likely, with a gene frequency of about 0.30 and a lifetime penetrance of about 70% for males and 90% for females. A gene frequency of about 0.05 and a penetrance of 25 to 30% would be required to account for the findings on a dominant hypothesis. <a href="#56" class="mim-tip-reference" title="Hodge, S. E., Rotter, J. I., Lange, K. L. <strong>A three-allele model for heterogeneity of juvenile onset insulin-dependent diabetes.</strong> Ann. Hum. Genet. 43: 399-409, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7053038/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7053038</a>] [<a href="https://doi.org/10.1111/j.1469-1809.1980.tb01573.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7053038">Hodge et al. (1980)</a> proposed a 3-allele model based on a susceptibility locus (S) tightly linked to the HLA complex. <a href="#133" class="mim-tip-reference" title="Thomson, G. <strong>A two locus model for juvenile diabetes.</strong> Ann. Hum. Genet. 43: 383-398, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7396412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7396412</a>] [<a href="https://doi.org/10.1111/j.1469-1809.1980.tb01572.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7396412">Thomson (1980)</a> espoused a 2-locus model. See <a href="/entry/125850">125850</a> for a clear example of an autosomal dominant type of diabetes mellitus: maturity-onset diabetes of the young (MODY). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14215758+7053038+7396412" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Cudworth, A. G., Woodrow, J. C. <strong>HL-A system and diabetes mellitus.</strong> Diabetes 24: 345-349, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/48487/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">48487</a>] [<a href="https://doi.org/10.2337/diab.24.4.345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="48487">Cudworth and Woodrow (1975)</a> found that the relative risk of IDDM was 2.12 for HLA-A 8 and 2.60 for W15. <a href="#115" class="mim-tip-reference" title="Rubinstein, P., Suciu-Foca, N., Nicholson, J. F. <strong>Genetics of juvenile diabetes mellitus: a recessive gene closely linked to HLA-D and with 50% penetrance.</strong> New Eng. J. Med. 297: 1036-1040, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/909549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">909549</a>] [<a href="https://doi.org/10.1056/NEJM197711102971905" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="909549">Rubinstein et al. (1977)</a> found that diabetic sibs shared their HLA genes with a significantly increased frequency, leading them to postulate a recessive gene linked to HLA (and specifically to HLA-D as indicated by 3 informative cases with recombination within the HLA). They estimated the penetrance at 50% because half the HLA-identical sibs of index cases were diabetic. This conclusion fits with published observations of 6-10% risk to sibs of patients when both parents are normal. As an appendix to their paper, they presented a table of risk to relatives on the basis of the above hypotheses. <a href="#5" class="mim-tip-reference" title="Barbosa, J., Chern, M. M., Noreen, H., Anderson, V. E., Yunis, E. J. <strong>Analysis of linkage between the major histocompatibility system and juvenile, insulin-dependent diabetes in multiplex families: reanalysis of data.</strong> J. Clin. Invest. 62: 492-495, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/670405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">670405</a>] [<a href="https://doi.org/10.1172/JCI109151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="670405">Barbosa et al. (1978)</a> also concluded that IDDM is a recessive with 50% penetrance and with linkage to HLA (theta = 0.13, lod = 3.98) on the basis of the study of 21 families with 2 or more affected sibs and normal parents. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=909549+670405+48487" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#140" class="mim-tip-reference" title="Vadheim, C. M., Rotter, J. I., Maclaren, N. K., Riley, W. J., Anderson, C. E. <strong>Preferential transmission of diabetic alleles within the HLA gene complex.</strong> New Eng. J. Med. 315: 1314-1318, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3490623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3490623</a>] [<a href="https://doi.org/10.1056/NEJM198611203152103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3490623">Vadheim et al. (1986)</a> pointed out that several studies suggested a higher incidence of IDDM among the offspring of affected males than among those of affected females. To test the hypothesis that differential transmission by the father of genes predisposed to diabetes may explain this phenomenon, <a href="#140" class="mim-tip-reference" title="Vadheim, C. M., Rotter, J. I., Maclaren, N. K., Riley, W. J., Anderson, C. E. <strong>Preferential transmission of diabetic alleles within the HLA gene complex.</strong> New Eng. J. Med. 315: 1314-1318, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3490623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3490623</a>] [<a href="https://doi.org/10.1056/NEJM198611203152103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3490623">Vadheim et al. (1986)</a> examined parent-to-offspring transmission of HLA haplotypes and DR alleles in 107 nuclear families in which a child had IDDM. They found that fathers with a DR4 allele were significantly more likely to transmit this allele to their diabetic or nondiabetic children than were mothers with a DR4 allele. No difference between parents was observed for HLA-DR3; however, DR3 was transmitted significantly more than 50% of the time from either parent. <a href="#44" class="mim-tip-reference" title="Field, L. L., Dizier, M.-H., Anderson, C. E., Spence, M. A., Rotter, J. I. <strong>HLA-dependent GM effects in insulin-dependent diabetes: evidence from pairs of affected siblings.</strong> Am. J. Hum. Genet. 39: 640-647, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3788976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3788976</a>]" pmid="3788976">Field et al. (1986)</a> reconfirmed the fact that sharing of 2 HLA haplotypes by sibs with diabetes mellitus was increased in comparison to mendelian expectations. Whereas sharing of GM-region genes was not different from mendelian expectations in the total sampled, affected pairs who shared 2 HLA haplotypes did show significantly increased sharing of GM-region genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3788976+3490623" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#77" class="mim-tip-reference" title="MacDonald, M. J., Gottschall, J., Hunter, J. B., Winter, K. L. <strong>HLA-DR4 in insulin-dependent diabetic parents and their diabetic offspring: a clue to dominant inheritance.</strong> Proc. Nat. Acad. Sci. 83: 7049-7053, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3489237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3489237</a>] [<a href="https://doi.org/10.1073/pnas.83.18.7049" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3489237">MacDonald et al. (1986)</a> studied families with IDDM in parent and child. The proportion of diabetic parents who transmitted DR4 to diabetic offspring (78%) was significantly higher (P less than 0.001) than the gene frequency of DR4 in the overall diabetic population (43%). The proportion of nondiabetic parents who transmitted DR4 to diabetic offspring (22%) was not significantly different from the gene frequency in the nondiabetic population but significantly lower (P less than 0.05) than the gene frequency in the overall IDDM population. This was taken to indicate a strong dominant effect of DR4. The proportion of nondiabetic parents who transmitted DR3 was similar to the gene frequency of DR3 in the overall diabetic population, but it was significantly higher than the gene frequency of DR 3 in the nondiabetic population (15%; P less than 0.005). The percentage of diabetic offspring who were DR3/DR4 (35%) was identical to that in the overall IDDM population (35%). <a href="#77" class="mim-tip-reference" title="MacDonald, M. J., Gottschall, J., Hunter, J. B., Winter, K. L. <strong>HLA-DR4 in insulin-dependent diabetic parents and their diabetic offspring: a clue to dominant inheritance.</strong> Proc. Nat. Acad. Sci. 83: 7049-7053, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3489237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3489237</a>] [<a href="https://doi.org/10.1073/pnas.83.18.7049" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3489237">MacDonald et al. (1986)</a> interpreted this to mean that DR3 plays an enhancing role, with DR4 playing the main role. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3489237" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#132" class="mim-tip-reference" title="Thomson, G., Robinson, W. P., Kuhner, M. K., Joe, S., MacDonald, M. J., Gottschall, J. L., Barbosa, J., Rich, S. S., Bertrams, J., Baur, M. P., Partanen, J., Tait, B. D., Schober, E., Mayr, W. R., Ludvigsson, J., Lindblom, B., Farid, N. R., Thompson, C., Deschamps, I. <strong>Genetic heterogeneity, modes of inheritance, and risk estimates for a joint study of Caucasians with insulin-dependent diabetes mellitus.</strong> Am. J. Hum. Genet. 43: 799-816, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3057885/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3057885</a>]" pmid="3057885">Thomson et al. (1988)</a> analyzed the results from 11 studies involving 1,792 Caucasian probands with IDDM. Antigen genotype frequencies in patients, transmission from affected parents to affected children, and the relative frequencies of HLA-DR3 and -DR4 homozygous patients all indicated that DR3 predisposes in a 'recessive'-like and DR4 in a 'dominant'-like or 'intermediate' fashion, after allowing for the synergistic effect of the 2 HLA types. DR2 showed a protective effect, DR1 and DRw8 showed predisposing effects, and DR5 showed a slight protective effect. They found evidence that only subsets of DR3 and DR4 are predisposing. The presence or absence of asp at position 57 of the DQ-beta gene was shown to be insufficient of itself in explaining the inheritance of IDDM. They suggested that the distinguishing features of the DR3-associated and DR4-associated predisposition remain to be identified at the molecular level. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3057885" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using an overall sib risk of 6%, <a href="#132" class="mim-tip-reference" title="Thomson, G., Robinson, W. P., Kuhner, M. K., Joe, S., MacDonald, M. J., Gottschall, J. L., Barbosa, J., Rich, S. S., Bertrams, J., Baur, M. P., Partanen, J., Tait, B. D., Schober, E., Mayr, W. R., Ludvigsson, J., Lindblom, B., Farid, N. R., Thompson, C., Deschamps, I. <strong>Genetic heterogeneity, modes of inheritance, and risk estimates for a joint study of Caucasians with insulin-dependent diabetes mellitus.</strong> Am. J. Hum. Genet. 43: 799-816, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3057885/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3057885</a>]" pmid="3057885">Thomson et al. (1988)</a> estimated that the risks for those sharing 2, 1, or 0 haplotypes are 12.9%, 4.5%, and 1.8%, respectively. The highest sib risk was 19.2% for sibs sharing 2 haplotypes with a DR3/DR4 proband. <a href="#45" class="mim-tip-reference" title="Field, L. L. <strong>Insulin-dependent diabetes mellitus: a model for the study of multifactorial disorders.</strong> Am. J. Hum. Genet. 43: 793-798, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3195582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3195582</a>]" pmid="3195582">Field (1988)</a> put this study in perspective with a discussion of other factors, including nongenetic factors. <a href="#118" class="mim-tip-reference" title="Sheehy, M. J., Scharf, S. J., Rowe, J. R., Neme de Gimenez, M. H., Meske, L. M., Erlich, H. A., Nepom, B. S. <strong>A diabetes-susceptible HLA haplotype is best defined by a combination of HLA-DR and -DQ alleles.</strong> J. Clin. Invest. 83: 830-835, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2784133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2784133</a>] [<a href="https://doi.org/10.1172/JCI113965" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2784133">Sheehy et al. (1989)</a> likewise concluded that susceptibility to diabetes is best defined by a combination of HLA-DR and HLA-DQ alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3195582+3057885+2784133" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of 266 unrelated white patients with IDDM, <a href="#3" class="mim-tip-reference" title="Baisch, J. M., Weeks, T., Giles, R., Hoover, M., Stastny, P., Capra, J. D. <strong>Analysis of HLA-DQ genotypes and susceptibility in insulin-dependent diabetes mellitus.</strong> New Eng. J. Med. 322: 1836-1841, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2348836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2348836</a>] [<a href="https://doi.org/10.1056/NEJM199006283222602" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2348836">Baisch et al. (1990)</a> extended the assessment of the role of HLA-DQ alleles in susceptibility to the disease. They used allele-specific oligonucleotide probes and PCR to study HLA-DQ beta-chain alleles. Two major findings emerged. First, HLA-DQw1.2 was protective; it was found in only 2.3% of IDDM patients and in 36.4% of controls. This was 'dominant protection,' i.e., it did not matter what other allele was present. Second, HLA-DQw8 increased the risk of IDDM and the effect was one of 'dominant susceptibility' except that persons who were HLA-DQw1.2/DQw8 had a relative risk of 0.37, demonstrating that the protective effect of HLA-DQw1.2 predominated over the effect of HLA-DQw8. <a href="#117" class="mim-tip-reference" title="Segall, M., Bach, F. H. <strong>HLA and disease: the perils of simplification.</strong> New Eng. J. Med. 322: 1879-1881, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2348840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2348840</a>] [<a href="https://doi.org/10.1056/NEJM199006283222609" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2348840">Segall and Bach (1990)</a> reviewed the significance of these findings. See also review by <a href="#138" class="mim-tip-reference" title="Todd, J. A. <strong>Genetic control of autoimmunity in type 1 diabetes.</strong> Immun. Today 11: 122-129, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2187469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2187469</a>] [<a href="https://doi.org/10.1016/0167-5699(90)90049-f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2187469">Todd (1990)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2187469+2348836+2348840" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The <a href="#39" class="mim-tip-reference" title="Eurodiab Ace Study Group and The Eurodiab Ace Substudy 2 Study Group. <strong>Familial risk of type I diabetes in European children.</strong> Diabetologia 41: 1151-1156, 1998. Note: Erratum: Diabetologia 42: 262 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9794100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9794100</a>] [<a href="https://doi.org/10.1007/s001250051044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9794100">Eurodiab Ace Study Group and the Eurodiab Ace Substudy 2 Study Group (1998)</a> studied the characteristics of familial type 1 diabetes mellitus, i.e., cases in which more than one affected first-degree relative was diagnosed before the age of 15 years. They used data from an international network of population-based registries and from a case-control study conducted in 8 of the network's centers. They found a positive association between the population incidence rate of type 1 diabetes and the prevalence of type 1 diabetes in fathers of affected children. A similar association was observed with the prevalence in sibs, but the association with prevalence in mothers was weaker and not significant. Pooling results from all centers showed that a greater proportion of fathers (3.4%) of affected children had type 1 diabetes than mothers (1.8%) giving a risk ratio of 1.8. Affected girls were more likely to have a father with type 1 diabetes than affected boys, but there was no evidence of a similar finding for mothers or sibs. Familial type 1 diabetes patients had a younger age at onset than nonfamilial patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9794100" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#68" class="mim-tip-reference" title="Krischer, J. P., Cuthbertson, D. D., Yu, L., Orban, T., Maclaren, N., Jackson, R., Winter, W. E., Schatz, D. A., Palmer, J. P., Eisenbarth, G. S., The Diabetes Prevention Trial-Type 1 Study Group. <strong>Screening strategies for the identification of multiple antibody-positive relatives of individuals with type 1 diabetes.</strong> J. Clin. Endocr. Metab. 88: 103-108, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12519837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12519837</a>] [<a href="https://doi.org/10.1210/jc.2002-020760" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12519837">Krischer et al. (2003)</a> determined the extent to which different screening strategies could identify a population of nondiabetic relatives of a proband with type 1 diabetes who had 2 or more immunologic markers from the group consisting of islet cell antibodies (ICA), microinsulin autoantibodies (MIAA), GAD65 (<a href="/entry/138275">138275</a>) autoantibodies (GAA), and ICA512 (<a href="/entry/601773">601773</a>) autoantibodies (ICA512AA). Screening for any 3 antibodies guaranteed that all multiple antibody-positive subjects were detected. Screening for 2 antibodies at once and testing for the remaining antibodies among those who were positive for 1 resulted in a sensitivity of 99% for GAA and ICA, 97% for GAA and MIAA or GAA and ICA512AA, 93% for ICA512AA and ICA, 92% for MIAA and ICA, and 73% for ICA512AA and MIAA. From a laboratory perspective, screenings for GAA, ICA512AA, and MIAA are semiautomated tests with high throughput that, if used as initial screen, would identify at first testing 67% of the 2.3% of multiple antibody-positive relatives (100% if antibody-positive subjects are subsequently tested for ICA) as well as 4.7% of relatives with a single biochemical autoantibody, some of whom may convert to multiple autoantibody positivity on follow-up. Testing for ICA among relatives with 1 biochemical antibody would identify the remaining 33% of multiple antibody-positive relatives. They concluded that further follow-up and analysis of actual progression to diabetes will be essential to define actual diabetes risk in this large cohort. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12519837" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#18" class="mim-tip-reference" title="Clerget-Darpoux, F., Bonaiti-Pellie, C., Deschamps, I., Hors, J., Feingold, N. <strong>Juvenile insulin-dependent diabetes: a possible susceptibility gene in interaction with HLA.</strong> Ann. Hum. Genet. 45: 199-206, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7316482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7316482</a>] [<a href="https://doi.org/10.1111/j.1469-1809.1981.tb00321.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7316482">Clerget-Darpoux et al. (1981)</a> concluded that the data in 30 multiplex families with IDDM best fitted a model with a susceptibility gene that was not linked to but interacted with the HLA system. Under 3 different genetic models for IDDM, <a href="#55" class="mim-tip-reference" title="Hodge, S. E., Anderson, C. E., Neiswanger, K., Field, L. L., Spence, M. A., Sparkes, R. S., Sparkes, M. C., Crist, M., Terasaki, P. I., Rimoin, D. L., Rotter, J. I. <strong>Close genetic linkage between diabetes mellitus and Kidd blood group.</strong> Lancet 318: 893-895, 1981. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6117683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6117683</a>] [<a href="https://doi.org/10.1016/s0140-6736(81)91391-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6117683">Hodge et al. (1981)</a> found evidence for linkage with 2 different sets of marker loci: HLA, properdin factor B, and glyoxalase-1 on chromosome 6, and Kidd blood group (then thought to be on chromosome 2, but later shown to be on chromosome 18). Thus, 2 distinct disease-susceptibility loci may be involved in IDDM, a situation also postulated for Graves disease (<a href="/entry/275000">275000</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7316482+6117683" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Bell, G. I., Horita, S., Karam, J. H. <strong>A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus.</strong> Diabetes 33: 176-183, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6363172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6363172</a>] [<a href="https://doi.org/10.2337/diab.33.2.176" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6363172">Bell et al. (1984)</a> described an association between IDDM and a polymorphic region in the 5-prime flanking region of the insulin gene (INS; <a href="/entry/176730">176730</a>). This polymorphism (<a href="#10" class="mim-tip-reference" title="Bell, G. I., Karam, J. H., Rutter, W. J. <strong>Polymorphic DNA region adjacent to the 5-prime end of the human insulin gene.</strong> Proc. Nat. Acad. Sci. 78: 5759-5763, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6272317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6272317</a>] [<a href="https://doi.org/10.1073/pnas.78.9.5759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6272317">Bell et al., 1981</a>) arises from a variable number of tandemly repeated (VNTR) 14-bp oligonucleotides. When divided into 3 size classes, a significant association was seen between the short-length (class I) alleles and IDDM. Several studies were unable to demonstrate linkage of these VNTR alleles to IDDM in families, but this may in part be attributable to the fact that the disease-associated allele is present at high frequency in the general population. Several disease-associated polymorphisms were identified and the boundaries of association were mapped to a region of 19 kb on 11p15.5. <a href="#43" class="mim-tip-reference" title="Ferns, G. A. A., Hitman, G. A., Trembath, R., Williams, L., Tarn, A., Gale, E. A., Galton, D. J. <strong>DNA polymorphic haplotypes on the short arm of chromosome 11 and the inheritance of type I diabetes mellitus.</strong> J. Med. Genet. 23: 210-216, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3014147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3014147</a>] [<a href="https://doi.org/10.1136/jmg.23.3.210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3014147">Ferns et al. (1986)</a> studied 14 families in which 13 had 2 cases of IDDM and found no linkage to polymorphic loci 5-prime to the insulin gene or to those 3-prime to the HRAS gene. Association with HLA was again found; persons who were HLA identical to the diabetic proband were more likely to be diabetic than those who were nonidentical. From studies of allele sharing in affected sib pairs, <a href="#27" class="mim-tip-reference" title="Cox, N. J., Baker, L., Spielman, R. S. <strong>Insulin-gene sharing in sib pairs with insulin-dependent diabetes mellitus: no evidence for linkage.</strong> Am. J. Hum. Genet. 42: 167-172, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2892397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2892397</a>]" pmid="2892397">Cox et al. (1988)</a> found evidence of HLA-linked susceptibility to IDDM but no evidence of a contribution of similar magnitude by the insulin-gene region. This failure of family studies to demonstrate linkage is difficult to reconcile with the association demonstrated between alleles at the VNTR locus in the 5-prime region of the insulin gene on 11p (<a href="#8" class="mim-tip-reference" title="Bell, G. I., Horita, S., Karam, J. H. <strong>A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus.</strong> Diabetes 33: 176-183, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6363172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6363172</a>] [<a href="https://doi.org/10.2337/diab.33.2.176" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6363172">Bell et al., 1984</a>; <a href="#9" class="mim-tip-reference" title="Bell, G. I., Karam, J. H., Raffel, L. J., Hitman, G. A., Yen, P. H., Galton, D. J., Bottazzo, G. F., Rotter, J. I., Thomson, G. <strong>Recessive inheritance for the insulin linked IDDM predisposing gene. (Abstract)</strong> Am. J. Hum. Genet. 37: A188, 1985."None>Bell et al., 1985</a>). <a href="#35" class="mim-tip-reference" title="Donald, J. A., Barendse, W., Cooper, D. W. <strong>Linkage studies of HLA and insulin gene restriction fragment length polymorphisms in families with IDDM.</strong> Genet. Epidemiol. 6: 77-81, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2567262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2567262</a>] [<a href="https://doi.org/10.1002/gepi.1370060115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2567262">Donald et al. (1989)</a> used DR and DQ RFLPs for linkage analysis and demonstrated very close linkage of an IDDM-susceptibility locus. No evidence was found of any effect of the insulin gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3014147+6272317+2567262+6363172+2892397" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#102" class="mim-tip-reference" title="Raum, D., Alper, C. A., Stein, R., Gabbay, K. H. <strong>Genetic marker for insulin-dependent diabetes mellitus.</strong> Lancet 313: 1208-1210, 1979. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/87677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">87677</a>] [<a href="https://doi.org/10.1016/s0140-6736(79)91895-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="87677">Raum et al. (1979)</a> found a rare genetic type of properdin factor B (F1) in 22.6% of patients with IDDM but in only 1.9% of the general population. If, as the authors suggested, this is an indication of linkage disequilibrium, not association, some populations should not show the relationship. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=87677" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Based on a study in mice (<a href="#98" class="mim-tip-reference" title="Prochazka, M., Leiter, E. H., Serreze, D. V., Coleman, D. L. <strong>Three recessive loci required for insulin-dependent diabetes in nonobese diabetic mice.</strong> Science 237: 286-289, 1987. Note: Erratum: Science 242: 945 only, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2885918/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2885918</a>] [<a href="https://doi.org/10.1126/science.2885918" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2885918">Prochazka et al., 1987</a>) it may be that corresponding recessive genes are located on chromosomes 6 and 11 in man; the THY1 (<a href="/entry/188230">188230</a>) and the APOA1 (<a href="/entry/107680">107680</a>) genes are on human 11q. By use of an affected sib pair method, <a href="#58" class="mim-tip-reference" title="Hyer, R. N., Julier, C., Buckley, J. D., Trucco, M., Rotter, J., Spielman, R., Barnett, A., Bain, S., Boitard, C., Deschamps, I., Todd, J. A., Bell, J. I., Lathrop, G. M. <strong>High-resolution linkage mapping for susceptibility genes in human polygenic disease: insulin-dependent diabetes mellitus and chromosome 11q.</strong> Am. J. Hum. Genet. 48: 243-257, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1990836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1990836</a>]" pmid="1990836">Hyer et al. (1991)</a> excluded the possibility of an IDDM susceptibility gene on 11q. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1990836+2885918" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#75" class="mim-tip-reference" title="Lucassen, A. M., Julier, C., Beressi, J.-P., Boitard, C., Froguel, P., Lathrop, M., Bell, J. I. <strong>Susceptibility to insulin dependent diabetes mellitus maps to a 4.1 kb segment of DNA spanning the insulin gene and associated VNTR.</strong> Nature Genet. 4: 305-310, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8358440/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8358440</a>] [<a href="https://doi.org/10.1038/ng0793-305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8358440">Lucassen et al. (1993)</a> presented a detailed sequence comparison of the predominant haplotypes found in the region of 19 kb on 11p15.5 in a population of French-Canadian IDDM patients and controls. Identification of polymorphisms, both associated and unassociated with IDDM, permitted a further definition of the region of association to 4.1 kb. Ten polymorphisms within this region were found to be in strong linkage disequilibrium with each other and extended across the insulin gene locus and the VNTR situated immediately 5-prime to the insulin gene. These represent a set of candidate disease polymorphisms, one or more of which may account for the susceptibility to IDDM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8358440" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using 96 affected sib pairs and a fluorescence-based linkage map of 290 marker loci (average spacing 11 cM), <a href="#34" class="mim-tip-reference" title="Davies, J. L., Kawaguchi, Y., Bennett, S. T., Copeman, J. B., Cordell, H. J., Pritchard, L. E., Reed, P. W., Gough, S. C. L., Jenkins, S. C., Palmer, S. M., Balfour, K. M., Rowe, B. R., Farrall, M., Barnett, A. H., Bain, S. C., Todd, J. A. <strong>A genome-wide search for human type 1 diabetes susceptibility genes.</strong> Nature 371: 130-136, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8072542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8072542</a>] [<a href="https://doi.org/10.1038/371130a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8072542">Davies et al. (1994)</a> searched the human genome for genes that predispose to type 1 (insulin-dependent) diabetes mellitus. A total of 18 different chromosomal regions showed some positive evidence of linkage to the disease, strongly suggesting that IDDM is inherited in a polygenic fashion. Although the authors determined that no genes are likely to have as large effects as IDDM1 (in the major histocompatibility complex on 6p21), significant linkage was confirmed in the insulin gene region on 11p15 (IDDM2; <a href="/entry/125852">125852</a>) and established to 11q (IDDM4; <a href="/entry/600319">600319</a>), 6q (<a href="/entry/600320">600320</a>), and possibly to chromosome 18. Possible candidate genes within regions of linkage include GAD1 (<a href="/entry/605363">605363</a>) and GAD2 (<a href="/entry/138275">138275</a>), which encode the enzyme glutamic acid decarboxylase; SOD2 (<a href="/entry/147460">147460</a>), which encodes superoxide dismutase; and the Kidd blood group locus. Linkage of IDDM susceptibility to the region of the FGF gene on chromosome 11q13 was also reported by <a href="#53" class="mim-tip-reference" title="Hashimoto, L., Habita, C., Beressi, J. P., Delepine, M., Besse, C., Cambon-Thomsen, A., Deschamps, I., Rotter, J. I., Djoulah, S., James, M. R., Froguel, P., Weissenbach, J., Lathrop, G. M., Julier, C. <strong>Genetic mapping of a susceptibility locus for insulin-dependent diabetes mellitus on chromosome 11q.</strong> Nature 371: 161-164, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8072544/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8072544</a>] [<a href="https://doi.org/10.1038/371161a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8072544">Hashimoto et al. (1994)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8072542+8072544" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Genetic analysis of a mouse model of major histocompatibility complex-associated autoimmune type 1 (insulin-dependent) diabetes mellitus showed that the disease is caused by a combination of a major effect at the MHC and at least 10 other susceptibility loci elsewhere in the genome (<a href="#106" class="mim-tip-reference" title="Risch, N., Ghosh, S., Todd, J. A. <strong>Statistical evaluation of multiple-locus linkage data in experimental species and relevance to human studies: application to nonobese diabetic (NOD) murine and human insulin-dependent diabetes mellitus (IDDM).</strong> Am. J. Hum. Genet. 53: 702-714, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8352278/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8352278</a>]" pmid="8352278">Risch et al., 1993</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8352278" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a genomewide scan of 93 affected sib pair families from the UK, <a href="#34" class="mim-tip-reference" title="Davies, J. L., Kawaguchi, Y., Bennett, S. T., Copeman, J. B., Cordell, H. J., Pritchard, L. E., Reed, P. W., Gough, S. C. L., Jenkins, S. C., Palmer, S. M., Balfour, K. M., Rowe, B. R., Farrall, M., Barnett, A. H., Bain, S. C., Todd, J. A. <strong>A genome-wide search for human type 1 diabetes susceptibility genes.</strong> Nature 371: 130-136, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8072542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8072542</a>] [<a href="https://doi.org/10.1038/371130a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8072542">Davies et al. (1994)</a> found a similar genetic basis for human type 1 diabetes, with a major component at the MHC locus (IDDM1) explaining 34% of the familial clustering of the disease. <a href="#79" class="mim-tip-reference" title="Mein, C. A., Esposito, L., Dunn, M. G., Johnson, G. C. L., Timms, A. E., Goy, J. V., Smith, A. N., Sebag-Montefiore, L., Merriman, M. E., Wilson, A. J., Pritchard, L. E., Cucca, F., Barnett, A. H., Bain, S. C., Todd, J. A. <strong>A search for type 1 diabetes susceptibility genes in families from the United Kingdom.</strong> Nature Genet. 19: 297-300, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662409/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662409</a>] [<a href="https://doi.org/10.1038/991" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9662409">Mein et al. (1998)</a> analyzed a further 263 multiplex families from the same population to provide a total UK dataset of 356 affected sib pair families. Only 4 regions of the genome outside IDDM1/MHC, which was still the only major locus detected, were not excluded, and 2 of these showed evidence of linkage: 10p13-p11 (maximum lod score = 4.7) and 16q22-q24 (maximum lod score = 3.4). They stated that these and other novel regions, including 14q12-q21 and 19p13-q13, could potentially harbor disease loci. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8072542+9662409" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Concannon, P., Gogolin-Ewens, K. J., Hinds, D. A., Wapelhorst, B., Morrison, V. A., Stirling, B., Mitra, M., Farmer, J., Williams, S. R., Cox, N. J., Bell, G. I., Risch, N., Spielman, R. S. <strong>A second-generation screen of the human genome for susceptibility to insulin-dependent diabetes mellitus.</strong> Nature Genet. 19: 292-296, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662408</a>] [<a href="https://doi.org/10.1038/985" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9662408">Concannon et al. (1998)</a> reported the results of a genome screen for linkage with IDDM and analyzed the data by multipoint linkage methods. An initial panel of 212 affected sib pairs were genotyped for 438 markers spanning all autosomes, and an additional 467 affected sib pairs were used for follow-up genotyping. Other than the well-established linkage with the HLA region at 6p21.3, they found only 1 region, located on 1q and not previously reported, where the lod score exceeded 3.0. Lods between 1.0 and 1.8 were found in 6 other regions, 3 of which had been reported in other studies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9662408" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Cox, N. J., Wapelhorst, B., Morrison, V. A., Johnson, L., Pinchuk, L., Spielman, R. S., Todd, J. A., Concannon, P. <strong>Seven regions of the genome show evidence of linkage to type 1 diabetes in a consensus analysis of 767 multiplex families.</strong> Am. J. Hum. Genet. 69: 820-830, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11507694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11507694</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11507694[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/323501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11507694">Cox et al. (2001)</a> reported a genome scan using a new collection of 225 multiplex families with type 1 diabetes and combining the data with those from previous genome scans (<a href="#34" class="mim-tip-reference" title="Davies, J. L., Kawaguchi, Y., Bennett, S. T., Copeman, J. B., Cordell, H. J., Pritchard, L. E., Reed, P. W., Gough, S. C. L., Jenkins, S. C., Palmer, S. M., Balfour, K. M., Rowe, B. R., Farrall, M., Barnett, A. H., Bain, S. C., Todd, J. A. <strong>A genome-wide search for human type 1 diabetes susceptibility genes.</strong> Nature 371: 130-136, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8072542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8072542</a>] [<a href="https://doi.org/10.1038/371130a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8072542">Davies et al., 1994</a>; <a href="#20" class="mim-tip-reference" title="Concannon, P., Gogolin-Ewens, K. J., Hinds, D. A., Wapelhorst, B., Morrison, V. A., Stirling, B., Mitra, M., Farmer, J., Williams, S. R., Cox, N. J., Bell, G. I., Risch, N., Spielman, R. S. <strong>A second-generation screen of the human genome for susceptibility to insulin-dependent diabetes mellitus.</strong> Nature Genet. 19: 292-296, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662408</a>] [<a href="https://doi.org/10.1038/985" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9662408">Concannon et al., 1998</a>; <a href="#79" class="mim-tip-reference" title="Mein, C. A., Esposito, L., Dunn, M. G., Johnson, G. C. L., Timms, A. E., Goy, J. V., Smith, A. N., Sebag-Montefiore, L., Merriman, M. E., Wilson, A. J., Pritchard, L. E., Cucca, F., Barnett, A. H., Bain, S. C., Todd, J. A. <strong>A search for type 1 diabetes susceptibility genes in families from the United Kingdom.</strong> Nature Genet. 19: 297-300, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662409/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662409</a>] [<a href="https://doi.org/10.1038/991" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9662409">Mein et al., 1998</a>). The combined sample of 831 affected sib pairs, all with both parents genotyped, provided 90% power to detect linkage. Three chromosome regions were identified that showed significant evidence of linkage with lod scores greater than 4: 6p21 (IDDM1); 11p15 (IDDM2); and 16q22-q24; 4 other regions showed suggestive evidence of linkage with lod scores of 2.2 or greater: 10p11 (IDDM10, <a href="/entry/601942">601942</a>); 2q31 (IDDM7, <a href="/entry/600321">600321</a>; IDDM12, <a href="/entry/601388">601388</a>; IDDM13, <a href="/entry/601318">601318</a>); 6q21 (IDDM15, <a href="/entry/601666">601666</a>); and 1q42. Exploratory analyses, taking into account the presence of specific high-risk HLA genotypes or affected sibs' ages at disease onset, provided evidence of linkage at several additional sites, including the putative IDDM8 (<a href="/entry/600883">600883</a>) locus on 6q27. The results indicated that much of the difficulty in mapping type 1 diabetes susceptibility genes results from inadequate sample sizes, and pointed to the value of international collaborations to assemble and analyze much larger datasets for linkage in complex diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8072542+9662408+9662409+11507694" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#96" class="mim-tip-reference" title="Paterson, A. D., Petronis, A. <strong>Age and sex based genetic locus heterogeneity in type 1 diabetes.</strong> J. Med. Genet. 37: 186-191, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10699054/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10699054</a>] [<a href="https://doi.org/10.1136/jmg.37.3.186" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10699054">Paterson and Petronis (2000)</a> used data from a genomewide linkage study of 356 affected sib pairs with type 1 diabetes to perform linkage analyses using parental origin of shared alleles in subgroups based on sex of affected sibs and age of diagnosis. They found that evidence for linkage to IDDM4 occurred predominantly from opposite sex sib pairs and that for linkage to a locus on chromosome 4q occurred in sibs where one was diagnosed before age 10 years and one after age 10. <a href="#96" class="mim-tip-reference" title="Paterson, A. D., Petronis, A. <strong>Age and sex based genetic locus heterogeneity in type 1 diabetes.</strong> J. Med. Genet. 37: 186-191, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10699054/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10699054</a>] [<a href="https://doi.org/10.1136/jmg.37.3.186" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10699054">Paterson and Petronis (2000)</a> concluded that these methods might help reduce locus heterogeneity in type 1 diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10699054" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using DNA from 253 Danish IDDM families, <a href="#11" class="mim-tip-reference" title="Bergholdt, R., Nerup, J., Pociot, F. <strong>Fine mapping of a region on chromosome 21q21.11-q22.3 showing linkage to type 1 diabetes.</strong> J. Med. Genet. 42: 17-25, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15635070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15635070</a>] [<a href="https://doi.org/10.1136/jmg.2004.022004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15635070">Bergholdt et al. (2005)</a> analyzed the chromosomal region 21q21.3-qter, which had been previously linked to IDDM by the <a href="#40" class="mim-tip-reference" title="European Consortium for IDDM Genome Studies. <strong>A genomewide scan for type 1-diabetes susceptibility in Scandinavian families: identification of new loci with evidence of interactions.</strong> Am. J. Hum. Genet. 69: 1301-1313, 2001. Note: Erratum: Am. J. Hum. Genet. 70: 1075 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11598829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11598829</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11598829[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/324341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11598829">European Consortium for IDDM Genome Studies (2001)</a>. Multipoint nonparametric linkage analysis showed a peak score of 3.61 at marker D21S1920 (p = 0.0002), and a '1-lod drop' interval of 6.3 Mb was identified between markers D21S261 and D21S270. No association was found with 74 coding SNPs from 32 candidate genes within the '1-lod drop' interval. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11598829+15635070" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using 2,360 SNP markers in the 4.4-Mb human major histocompatibility complex (MHC) locus and the adjacent 493 kb centromeric to the MHC, <a href="#109" class="mim-tip-reference" title="Roach, J. C., Deutsch, K., Li, S., Siegel, A. F., Bekris, L. M., Einhaus, D. C., Sheridan, C. M., Glusman, G., Hood, L., Lernmark, A., Janer, M. <strong>Genetic mapping at 3-kilobase resolution reveals inositol 1,4,5-triphosphate receptor 3 as a risk factor for type 1 diabetes in Sweden.</strong> Am. J. Hum. Genet. 79: 614-627, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16960798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16960798</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16960798[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/507876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16960798">Roach et al. (2006)</a> mapped the genetic influences for type 1 diabetes in 2 Swedish samples. They confirmed previous studies showing association with T1D in the MHC, most significantly near HLA-DR/DQ. In the region centromeric to the MHC, they identified a peak of association within the inositol 1,4,5-triphosphate receptor 3 gene (ITPR3; <a href="/entry/147267">147267</a>). The most significant single SNP in this region was at the center of the ITPR3 peak of association. The estimated population-attributable risk of 21.6% suggested that variation within ITPR3 reflects an important contribution to T1D in Sweden. Two-locus regression analysis supported an influence of ITPR3 variation on T1D that is distinct from that of any MHC class II gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16960798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The <a href="#147" class="mim-tip-reference" title="Wellcome Trust Case Control Consortium. <strong>Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.</strong> Nature 447: 661-678, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17554300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17554300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17554300[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature05911" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17554300">Wellcome Trust Case Control Consortium (2007)</a> described a joint genomewide association study using the Affymetrix GeneChip 500K Mapping Array Set, undertaken in the British population, which examined approximately 2,000 individuals and a shared set of approximately 3,000 controls for each of 7 major diseases. Case-control comparisons identified 7 independent association signals in type 1 diabetes at p values of less than 5.0 x 10(-7). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17554300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of 4,000 individuals with type 1 diabetes, 5,000 controls, and 2,997 family trios independent of the <a href="#147" class="mim-tip-reference" title="Wellcome Trust Case Control Consortium. <strong>Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.</strong> Nature 447: 661-678, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17554300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17554300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17554300[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature05911" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17554300">Wellcome Trust Case Control Consortium (2007)</a> study, <a href="#137" class="mim-tip-reference" title="Todd, J. A., Walker, N. M., Cooper, J. D., Smyth, D. J., Downes, K., Plagnol, V., Bailey, R., Nejentsev, S., Field, S. F., Payne, F., Lowe, C. E., Szeszko, J. S., and 30 others. <strong>Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes.</strong> Nature Genet. 39: 857-864, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17554260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17554260</a>] [<a href="https://doi.org/10.1038/ng2068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17554260">Todd et al. (2007)</a> confirmed the previously reported associations of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2542151;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2542151</a> in the PTPN2 gene (<a href="/entry/176887">176887</a>) on chromosome 18p11, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs17696736;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs17696736</a> in the C12ORF30 gene on chromosome 12q24, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2292239;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2292239</a> in the ERBB3 gene (<a href="/entry/190151">190151</a>) on chromosome 12q13, and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12708716;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12708716</a> in the KIAA0350 gene (CLEC16A; <a href="/entry/611303">611303</a>) on chromosome 16p13 (p less than or equal to 10(-9); combined with WTCCC p less than or equal to 1.15 x 10(-14)), leaving 8 regions with small effects or false-positive associations. The association with <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs17696736;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs17696736</a> led to the identification of a nonsynonymous SNP (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3184504;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3184504</a>) in the SH2B3 gene (<a href="/entry/605093">605093</a>) that was sufficient to model the association of the entire region (p = 1.73 x 10(-21); see IDDM20, <a href="/entry/612520">612520</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17554260+17554300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To identify genetic factors that increase the risk of type 1 diabetes, <a href="#51" class="mim-tip-reference" title="Hakonarson, H., Grant, S. F. A., Bradfield, J. P., Marchand, L., Kim, C. E., Glessner, J. T., Grabs, R., Casalunovo, T., Taback, S. P., Frackelton, E. C., Lawson, M. L., Robinson, L. J., and 11 others. <strong>A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene.</strong> Nature 448: 591-594, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17632545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17632545</a>] [<a href="https://doi.org/10.1038/nature06010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17632545">Hakonarson et al. (2007)</a> performed a genomewide association study in a large pediatric cohort of European descent. In addition to confirming previously identified loci, they found that type 1 diabetes was significantly associated with variation within a 233-kb linkage disequilibrium block on chromosome 16p13 that contains the KIAA0350 gene, which is predicted to encode a sugar-binding, C-type lectin. Three common noncoding variants of this gene (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2903692;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2903692</a>, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs725613;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs725613</a>, and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs17673553;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs17673553</a>) in strong linkage disequilibrium reached genomewide significance for association with type 1 diabetes. A subsequent transmission disequilibrium test replication study in an independent cohort confirmed the association. The combined P values for these SNPs ranged from 2.74 x 10(-5) to 6.7 x 10(-7). <a href="#51" class="mim-tip-reference" title="Hakonarson, H., Grant, S. F. A., Bradfield, J. P., Marchand, L., Kim, C. E., Glessner, J. T., Grabs, R., Casalunovo, T., Taback, S. P., Frackelton, E. C., Lawson, M. L., Robinson, L. J., and 11 others. <strong>A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene.</strong> Nature 448: 591-594, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17632545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17632545</a>] [<a href="https://doi.org/10.1038/nature06010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17632545">Hakonarson et al. (2007)</a> noted that the <a href="#147" class="mim-tip-reference" title="Wellcome Trust Case Control Consortium. <strong>Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.</strong> Nature 447: 661-678, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17554300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17554300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17554300[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature05911" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17554300"> Wellcome Trust Case Control Consortium (2007)</a> had identified the KIAA0350 gene as a type 1 diabetes locus in a genomewide association study. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17554300+17632545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#121" class="mim-tip-reference" title="Smyth, D. J., Plagnol, V., Walker, N. M., Cooper, J. D., Downes, K., Yang, J. H. M., Howson, J. M. M., Stevens, H., McManus, R., Wijmenga, C., Heap, G. A., Dubois, P. C., Clayton, D. G., Hunt, K. A., van Heel, D. A., Todd, J. A. <strong>Shared and distinct genetic variants in type 1 diabetes and celiac disease.</strong> New Eng. J. Med. 359: 2767-2777, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19073967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19073967</a>] [<a href="https://doi.org/10.1056/NEJMoa0807917" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19073967">Smyth et al. (2008)</a> evaluated the association between type 1 diabetes and 8 loci related to the risk of celiac disease in 8,064 patients with type 1 diabetes, 2,828 families providing 3,064 parent-child trios, and 9,339 controls. The authors found significant association between type 1 diabetes and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1738074;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1738074</a> in the TAGAP gene on chromosome 6q25 (see IDDM21, <a href="/entry/612521">612521</a>) and confirmed association with <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3184504;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3184504</a> in the SH2B3 gene (<a href="/entry/605093">605093</a>) on chromosome 12q24 (see IDDM20, <a href="/entry/612520">612520</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19073967" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Cooper, J. D., Smyth, D. J., Smiles, A. M., Plagnol, V., Walker, N. M., Allen, J. E., Downes, K., Barrett, J. C., Healy, B. C., Mychaleckyj, J. C., Warram, J. H., Todd, J. A. <strong>Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci.</strong> Nature Genet. 40: 1399-1401, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18978792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18978792</a>] [<a href="https://doi.org/10.1038/ng.249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18978792">Cooper et al. (2008)</a> performed a metaanalysis of 3 genomewide association studies, combining British type 1 diabetes (T1D) case-control data (<a href="#147" class="mim-tip-reference" title="Wellcome Trust Case Control Consortium. <strong>Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.</strong> Nature 447: 661-678, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17554300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17554300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17554300[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature05911" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17554300">Wellcome Trust Case Control Consortium, 2007</a>) with T1D cases from the Genetics of Kidneys in Diabetes study (<a href="#82" class="mim-tip-reference" title="Mueller, P. W., Rogus, J. J., Cleary, P. A., Zhao, Y., Smiles, A. M., Steffes, M. W., Bucksa, J., Gibson, T. B., Cordovado, S. K., Krolewski, A. S., Nierras, C. R., Warram, J. H. <strong>Genetics of kidneys in diabetes (GoKinD) study: a genetics collection available for identifying genetic susceptibility factors for diabetic nephropathy in type 1 diabetes.</strong> J. Am. Soc. Nephrol. 17: 1782-1790, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16775037/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16775037</a>] [<a href="https://doi.org/10.1681/ASN.2005080822" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16775037">Mueller et al., 2006</a>) for a total of 3,561 cases and 4,646 controls. <a href="#23" class="mim-tip-reference" title="Cooper, J. D., Smyth, D. J., Smiles, A. M., Plagnol, V., Walker, N. M., Allen, J. E., Downes, K., Barrett, J. C., Healy, B. C., Mychaleckyj, J. C., Warram, J. H., Todd, J. A. <strong>Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci.</strong> Nature Genet. 40: 1399-1401, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18978792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18978792</a>] [<a href="https://doi.org/10.1038/ng.249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18978792">Cooper et al. (2008)</a> found support for a previously detected locus on chromosome 4q27 at <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs17388568;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs17388568</a> (p = 1.87 x 10(-8); see IDDM23, <a href="/entry/612622">612622</a>). After genotyping an additional 6,225 cases, 6,946 controls, and 2,828 families, they also found evidence for 4 previously unknown and distinct risk loci: at <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11755527;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs11755527</a> in intron 3 of the BACH2 gene (<a href="/entry/605394">605394</a>) on chromosome 6q15 (p = 4.7 x 10(-12)); at <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs947474;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs947474</a>, near the PRKCQ gene (<a href="/entry/600448">600448</a>) on chromosome 10p15 (p = 3.7 x 10(-9)); at <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3825932;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3825932</a> in intron 1 of the CTSH gene (<a href="/entry/116820">116820</a>) on chromosome 15q24 (p = 3.2 x 10(-15)); and at <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs229541;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs229541</a>, located between the C1QTNF6 and SSTR3 (<a href="/entry/182453">182453</a>) genes on chromosome 22q13 (p = 2.0 x 10(-8)). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16775037+17554300+18978792" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Barrett, J. C., Clayton, D. G., Concannon, P., Akolkar, B., Cooper, J. D., Erlich, H. A., Julier, C., Morahan, G., Nerup, J., Nierras, C., Plagnol, V., Pociot, F., Schuilenburg, H., Smyth, D. J., Stevens, H., Todd, J. A., Walker, N. M., Rich, S. S., Type 1 Diabetes Genetics Consortium. <strong>Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes.</strong> Nature Genet. 41: 703-707, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19430480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19430480</a>] [<a href="https://doi.org/10.1038/ng.381" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19430480">Barrett et al. (2009)</a> reported the findings of a genomewide association study of type 1 diabetes, combined in a metaanalysis with 2 previously published studies (<a href="#147" class="mim-tip-reference" title="Wellcome Trust Case Control Consortium. <strong>Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.</strong> Nature 447: 661-678, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17554300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17554300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17554300[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature05911" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17554300">Wellcome Trust Case Control Consortium, 2007</a>; <a href="#23" class="mim-tip-reference" title="Cooper, J. D., Smyth, D. J., Smiles, A. M., Plagnol, V., Walker, N. M., Allen, J. E., Downes, K., Barrett, J. C., Healy, B. C., Mychaleckyj, J. C., Warram, J. H., Todd, J. A. <strong>Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci.</strong> Nature Genet. 40: 1399-1401, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18978792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18978792</a>] [<a href="https://doi.org/10.1038/ng.249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18978792">Cooper et al., 2008</a>). The total sample set included 7,514 cases and 9,045 reference samples. Forty-one distinct genomic locations provided evidence for association with type 1 diabetes in the metaanalysis (P less than 10(-6)). Using an analysis that combined comparisons over the 3 studies, they confirmed several previously reported associations, including <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2476601;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2476601</a> at chromosome 1p13.2 (P = 8.5 x 10(-85)), <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs7111341;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs7111341</a> at 11p15.5 (P = 4.4 x 10(-48)), <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2292239;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2292239</a> at 12q13.2 (P = 2.2 x 10(-25)), and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3184504;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3184504</a> at 12q24.12 (P = 2.8 x 10(-27)). <a href="#7" class="mim-tip-reference" title="Barrett, J. C., Clayton, D. G., Concannon, P., Akolkar, B., Cooper, J. D., Erlich, H. A., Julier, C., Morahan, G., Nerup, J., Nierras, C., Plagnol, V., Pociot, F., Schuilenburg, H., Smyth, D. J., Stevens, H., Todd, J. A., Walker, N. M., Rich, S. S., Type 1 Diabetes Genetics Consortium. <strong>Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes.</strong> Nature Genet. 41: 703-707, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19430480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19430480</a>] [<a href="https://doi.org/10.1038/ng.381" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19430480">Barrett et al. (2009)</a> further tested 27 novel regions in an independent set of 4,267 cases and 4,463 controls, and 2,319 affected sib pair families. Of these, 18 regions were replicated (P less than 0.01; overall P less than 5 x 10(-8)) and 4 additional regions provided nominal evidence of replication. A region on 1q32.1 represented by SNP <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3024505;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3024505</a> (combined P = 1.9 x 10(-9)) contains the immunoregulatory cytokine genes IL10 (<a href="/entry/124092">124092</a>), IL19 (<a href="/entry/605687">605687</a>), and IL20 (<a href="/entry/605619">605619</a>). The strongest evidence of association among these 27 novel regions was achieved at <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs10509540;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs10509540</a> on chromosome 10q23.31; see IDDM24, <a href="/entry/613006">613006</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17554300+19430480+18978792" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#145" class="mim-tip-reference" title="Wallace, C., Smyth, D. J., Maisuria-Armer, M., Walker, N. M., Todd, J. A., Clayton, D. G. <strong>The imprinted DLK1-MEG3 gene region on chromosome 14q32.2 alters susceptibility to type 1 diabetes.</strong> Nature Genet. 42: 68-71, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19966805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19966805</a>] [<a href="https://doi.org/10.1038/ng.493" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19966805">Wallace et al. (2010)</a> used imputation to assess association with T1D across 2.6 million SNPs in a total of 7,514 cases and 9,405 controls from 3 existing GWA studies (<a href="#147" class="mim-tip-reference" title="Wellcome Trust Case Control Consortium. <strong>Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.</strong> Nature 447: 661-678, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17554300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17554300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17554300[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature05911" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17554300">Wellcome Trust Case Control Consortium, 2007</a>; <a href="#23" class="mim-tip-reference" title="Cooper, J. D., Smyth, D. J., Smiles, A. M., Plagnol, V., Walker, N. M., Allen, J. E., Downes, K., Barrett, J. C., Healy, B. C., Mychaleckyj, J. C., Warram, J. H., Todd, J. A. <strong>Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci.</strong> Nature Genet. 40: 1399-1401, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18978792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18978792</a>] [<a href="https://doi.org/10.1038/ng.249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18978792">Cooper et al., 2008</a>; <a href="#7" class="mim-tip-reference" title="Barrett, J. C., Clayton, D. G., Concannon, P., Akolkar, B., Cooper, J. D., Erlich, H. A., Julier, C., Morahan, G., Nerup, J., Nierras, C., Plagnol, V., Pociot, F., Schuilenburg, H., Smyth, D. J., Stevens, H., Todd, J. A., Walker, N. M., Rich, S. S., Type 1 Diabetes Genetics Consortium. <strong>Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes.</strong> Nature Genet. 41: 703-707, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19430480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19430480</a>] [<a href="https://doi.org/10.1038/ng.381" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19430480">Barrett et al., 2009</a>). They obtained evidence of an association at <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs941576;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs941576</a>, a marker in the imprinted region of chromosome 14q32.2, for paternally inherited risk of T1D (p = 1.62 x 10(-10); ratio of allelic affects for paternal versus maternal transmissions = 0.75). <a href="#145" class="mim-tip-reference" title="Wallace, C., Smyth, D. J., Maisuria-Armer, M., Walker, N. M., Todd, J. A., Clayton, D. G. <strong>The imprinted DLK1-MEG3 gene region on chromosome 14q32.2 alters susceptibility to type 1 diabetes.</strong> Nature Genet. 42: 68-71, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19966805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19966805</a>] [<a href="https://doi.org/10.1038/ng.493" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19966805">Wallace et al. (2010)</a> suggested that <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs941576;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs941576</a>, which is located within intron 6 of the maternally expressed noncoding RNA gene MEG3 (<a href="/entry/605636">605636</a>), or another nearby variant alters the regulation of the neighboring functional candidate gene DLK1 (<a href="/entry/176290">176290</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19430480+17554300+19966805+18978792" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Inflammatory bowel disease (see <a href="/entry/266600">266600</a>), including Crohn disease (CD) and ulcerative colitis (UC), and T1D are autoimmune diseases that may share common susceptibility pathways. <a href="#146" class="mim-tip-reference" title="Wang, K., Baldassano, R., Zhang, H., Qu, H.-Q., Imielinski, M., Kugathasan, S., Annese, V., Dubinsky, M., Rotter, J. I., Russell, R. K., Bradfield, J. P., Sleiman, P. M. A., and 22 others. <strong>Comparative genetic analysis of inflammatory bowel disease and type 1 diabetes implicates multiple loci with opposite effects.</strong> Hum. Molec. Genet. 19: 2059-2067, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20176734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20176734</a>] [<a href="https://doi.org/10.1093/hmg/ddq078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20176734">Wang et al. (2010)</a> examined known susceptibility loci for these diseases in a cohort of 1,689 CD cases, 777 UC cases, 989 T1D cases, and 6,197 shared control subjects of European ancestry. Multiple previously unreported or unconfirmed disease-loci associations were identified, including CD loci (ICOSLG, <a href="/entry/605717">605717</a>; TNFSF15, <a href="/entry/604052">604052</a>) and T1D loci (TNFAIP3; <a href="/entry/191163">191163</a>) that conferred UC risk; UC loci (HERC2, <a href="/entry/605837">605837</a>; IL26, <a href="/entry/605679">605679</a>) that conferred T1D risk; and UC loci (IL10, <a href="/entry/124092">124092</a>; CCNY, <a href="/entry/612786">612786</a>) that conferred CD risk. T1D risk alleles residing at the PTPN22 (<a href="/entry/600716">600716</a>), IL27 (<a href="/entry/608273">608273</a>), IL18RAP (<a href="/entry/604509">604509</a>), and IL10 loci protected against CD. The strongest risk alleles for T1D within the major histocompatibility complex (MHC) conferred strong protection against CD and UC. The authors suggested that many loci involved in autoimmunity may be under a balancing selection due to antagonistic pleiotropic effects, and variants with opposite effects on different diseases may facilitate the maintenance of common susceptibility alleles in human populations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20176734" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>HLA Associations</em></strong></p><p>
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IDDM, although called the juvenile-onset type of diabetes, has its onset after the age of 20 years in 50% of cases. <a href="#14" class="mim-tip-reference" title="Caillat-Zucman, S., Garchon, H.-J., Timsit, J., Assan, R., Boitard, C., Djilali-Saiah, I., Bougneres, P., Bach, J.-F. <strong>Age-dependent HLA genetic heterogeneity of type 1 insulin-dependent diabetes mellitus.</strong> J. Clin. Invest. 90: 2242-2250, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1469084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1469084</a>] [<a href="https://doi.org/10.1172/JCI116110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1469084">Caillat-Zucman et al. (1992)</a> investigated whether the association of IDDM with certain HLA alleles, well-documented in pediatric patients, also holds for adults. Interestingly, they found quite different HLA class II gene profiles, with a significantly higher percentage of non-DR3/non-DR4 genotypes and a lower percentage of DR3/4 genotypes in older patients. Although the non-DR3/non-DR4 patients presented clinically as IDDM, they showed a lower frequency of islet cell antibodies (ICA) at diagnosis and a significantly milder insulin deficiency. These data (1) suggest these subjects probably represent a particular subset of IDDM patients in whom frequency increases with age; (2) confirm the genetic heterogeneity of IDDM; and (3) prompt caution in extrapolating the genetic concepts derived from childhood IDDM to adult patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1469084" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#89" class="mim-tip-reference" title="Nerup, J., Platz, P., Anderson, O. O., Christy, M., Lyngsoe, J., Poulsen, J. E., Ryder, L. P., Nielsen, L. S., Thomsen, M., Svejgaard, A. <strong>HL-A antigens and diabetes mellitus.</strong> Lancet 304: 864-866, 1974. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4137711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4137711</a>] [<a href="https://doi.org/10.1016/s0140-6736(74)91201-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4137711">Nerup et al. (1974)</a> found that IDDM (but not NIDDM) is associated with 2 particular HLA-A types (<a href="/entry/142800">142800</a>)--HLA-A8 and W15. <a href="#152" class="mim-tip-reference" title="Woodrow, J. C., Cudworth, A. G. <strong>HL-A8 and W15 in diabetes mellitus. (Letter)</strong> Lancet 305: 803 only, 1975. Note: Originally Volume I.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/48026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">48026</a>] [<a href="https://doi.org/10.1016/s0140-6736(75)92467-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="48026">Woodrow and Cudworth (1975)</a> interpreted the association of HLA-A8 and W15 with IDDM as resulting from linkage disequilibrium between genes for these antigens and a gene determining susceptibility of diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=48026+4137711" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To test for linkage between HLA and a locus for susceptibility to this disease, <a href="#19" class="mim-tip-reference" title="Clerget-Darpoux, F., Bonaiti-Pellie, C., Hors, J., Deschamps, I., Feingold, N. <strong>Application of the lod score method to detection of linkage between HLA and juvenile insulin-dependent diabetes.</strong> Clin. Genet. 18: 51-57, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6998613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6998613</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1980.tb01365.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6998613">Clerget-Darpoux et al. (1980)</a> studied 28 informative families with at least 1 child suffering from juvenile-onset IDDM. The 28 families were pooled with 21 from the literature and autosomal recessive inheritance was assumed. Maximum lod scores (6.00 to 7.36) were obtained for recombination fractions from 4% to 16%, according to the level of assumed penetrance (from 90% down to 10%). These high estimates of the recombination fraction are not consistent with the hypothesis that the association between IDDM and specific HLA haplotypes is a consequence of simple linkage disequilibrium between HLA and a susceptibility locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6998613" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#122" class="mim-tip-reference" title="Spielman, R. S., Baker, L., Zmijewski, C. M. <strong>Gene dosage and susceptibility to insulin-dependent diabetes.</strong> Ann. Hum. Genet. 44: 135-150, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6459051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6459051</a>] [<a href="https://doi.org/10.1111/j.1469-1809.1980.tb00954.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6459051">Spielman et al. (1980)</a> did HLA-typing on all members of 33 families in which 2 or more sibs had IDDM. They interpreted the results as supporting the hypothesis that, closely linked to the HLA region, there is a locus (symbolized S by them) for susceptibility to insulin-dependent diabetes. (S(d) was their symbol for the susceptibility allele and S(a) for all other alleles.) They estimated penetrance for the homozygote for S(d) to be 71% and for the heterozygote 6.5%. The recombination fraction between S and HLA was estimated to be under 3%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6459051" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#114" class="mim-tip-reference" title="Rubinstein, P., Ginsberg-Fellner, F., Falk, C. <strong>Genetics of type I diabetes mellitus: a single, recessive predisposition gene mapping between HLA-B and GLO, with an appendix on the estimation of selection bias by C. Falk.</strong> Am. J. Hum. Genet. 33: 865-882, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7034534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7034534</a>]" pmid="7034534">Rubinstein et al. (1981)</a> analyzed 3 sets of published data on HLA-typed families with IDDM in which no significant heterogeneity was detected. Autosomal recessive inheritance and incomplete penetrance were assumed. A maximum lod score of 7.40 at theta = 0.05 was found. The segregation of HLA and GLO in 5 affected sib pairs (4 of the 5 pairs were HLA-identical and GLO-different), in which one of the sibs carried an HLA-GLO recombinant, placed the IDDM locus closer to HLA than to GLO. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7034534" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#38" class="mim-tip-reference" title="Dunsworth, T. S., Rich, S. S., Morton, N. E., Barbosa, J. J. <strong>Heterogeneity of insulin dependent diabetes--new evidence.</strong> Clin. Genet. 21: 233-236, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6955075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6955075</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1982.tb00756.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6955075">Dunsworth et al. (1982)</a> performed complex segregation and linkage analysis in 182 families with at least 1 IDDM proband. All families were typed for HLA-B antigens and 118 for HLA-DR. The recessive model best fitted the data, with the maximum likelihood estimate of recombination between HLA-DR and the diabetes susceptibility factor being 0.019. Substantial heterogeneity was suggested; the smallest recombination was for families whose probands had 2 high-risk D alleles. Using RFLPs of the HLA-DR-alpha gene, <a href="#125" class="mim-tip-reference" title="Stetler, D., Grumet, F. C., Erlich, H. A. <strong>Polymorphic restriction endonuclease sites linked to the HLA-DR-alpha gene: localization and use as genetic markers of insulin-dependent diabetes.</strong> Proc. Nat. Acad. Sci. 82: 8100-8104, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2999792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2999792</a>] [<a href="https://doi.org/10.1073/pnas.82.23.8100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2999792">Stetler et al. (1985)</a> could show a higher association than is found with serologic markers. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6955075+2999792" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#105" class="mim-tip-reference" title="Rich, S. S., Green, A., Morton, N. E., Barbosa, J. <strong>A combined segregation and linkage analysis of insulin-dependent diabetes mellitus.</strong> Am. J. Hum. Genet. 40: 237-249, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3578273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3578273</a>]" pmid="3578273">Rich et al. (1987)</a> studied linkage of IDDM with HLA and factor B (<a href="/entry/138470">138470</a>) in combination with segregation analysis. They found evidence of strong linkage disequilibrium with the B-BF-D haplotype, with IDDM probably tightly linked to HLA-DR. The recombination fraction between the postulated major locus for IDDM and HLA was 0 in all models. They concluded that the best fitting genetic model of diabetic susceptibility is that of a single major locus with 'near recessivity' on a scale of standardized genetic liability, with a gene frequency of the IDDM susceptibility allele of approximately 14%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3578273" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#61" class="mim-tip-reference" title="Julier, C., Hyer, R. N., Davies, J., Merlin, F., Soularue, P., Briant, L., Cathelineau, G., Deschamps, I., Rotter, J. I., Froguel, P., Boitard, C., Bell, J. I., Lathrop, G. M. <strong>Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility.</strong> Nature 354: 155-159, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1944595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1944595</a>] [<a href="https://doi.org/10.1038/354155a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1944595">Julier et al. (1991)</a> studied polymorphisms of INS and neighboring loci in random patients with diabetes, IDDM multiplex families, and controls. They found that HLA-DR4-positive diabetics showed an increased risk associated with common variants at polymorphic sites in a 19-kb segment spanned by the 5-prime INS VNTR and the third intron of the gene for insulin-like growth factor II (<a href="/entry/147470">147470</a>). In multiplex families the IDDM-associated alleles for polymorphisms in this region were transmitted preferentially to HLA-DR4-positive diabetic offspring from heterozygous parents. The effect was strongest in paternal meioses, suggesting a possible role for maternal imprinting. <a href="#61" class="mim-tip-reference" title="Julier, C., Hyer, R. N., Davies, J., Merlin, F., Soularue, P., Briant, L., Cathelineau, G., Deschamps, I., Rotter, J. I., Froguel, P., Boitard, C., Bell, J. I., Lathrop, G. M. <strong>Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility.</strong> Nature 354: 155-159, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1944595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1944595</a>] [<a href="https://doi.org/10.1038/354155a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1944595">Julier et al. (1991)</a> suggested that the results strongly support the existence of a gene or genes affecting HLA-DR4 IDDM susceptibility in a 19-kb region of INS-IGF2. Their approach may be useful in mapping susceptibility loci in other common diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1944595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The fact that the association between IDDM and certain HLA-DQ alleles is even stronger than that with certain DR alleles and that there is little association with HLA-DP provides a boundary of disease association to the 430 kb between DQ and DP. In further studies of disease association with TAP (transporter associated with antigen processing) genes (<a href="/entry/170260">170260</a>), which map approximately midway between DP and DQ, <a href="#60" class="mim-tip-reference" title="Jackson, D. G., Capra, J. D. <strong>TAP1 alleles in insulin-dependent diabetes mellitus: a newly defined centromeric boundary of disease susceptibility.</strong> Proc. Nat. Acad. Sci. 90: 11079-11083, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8248212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8248212</a>] [<a href="https://doi.org/10.1073/pnas.90.23.11079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8248212">Jackson and Capra (1993)</a> found a higher association of a TAP allele with IDDM than with any single HLA-DP allele but the risk was lower than with HLA-DQB1*0302. These data provided new limits for IDDM susceptibility to the 190-kb interval between TAP1 and HLA-DQB1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8248212" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 2-stage approach to fine mapping, <a href="#54" class="mim-tip-reference" title="Herr, M., Dudbridge, F., Zavattari, P., Cucca, F., Guja, C., March, R., Campbell, R. D., Barnett, A. H., Bain, S. C., Todd, J. A., Koeleman, B. P. C. <strong>Evaluation of fine mapping strategies for a multifactorial disease locus: systematic linkage and association analysis of IDDM1 in the HLA region on chromosome 6p21.</strong> Hum. Molec. Genet. 9: 1291-1301, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10814711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10814711</a>] [<a href="https://doi.org/10.1093/hmg/9.9.1291" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10814711">Herr et al. (2000)</a> evaluated linkage in 385 affected sib-pair families using 13 evenly spaced polymorphic microsatellite markers spanning 14 Mb. Evidence of disease association was found for D6S2444, located within the 95% confidence interval of 1.7 cM obtained by linkage. Analysis of an additional 12 flanking markers revealed a highly specific region of 570 kb associated with disease that included the HLA class II genes. The peak of association was as close as 85 kb centromeric of HLA-DQB1. Recombination within the major histocompatibility complex was rare and nearly absent in the class III region. The authors concluded that the majority of disease association in the region can be explained by linkage disequilibrium with the class II susceptibility genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10814711" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#50" class="mim-tip-reference" title="Greenbaum, C. J., Schatz, D. A., Cutherbertson, D., Zeidler, A., Eisenbarth, G. S., Krischer, J. P. <strong>Islet cell antibody-positive relatives with human leukocyte antigen DQA1*0102, DQB1*0602: identification by the Diabetes Prevention Trial-Type 1.</strong> J. Clin. Endocr. Metab. 85: 1255-1260, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10720072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10720072</a>] [<a href="https://doi.org/10.1210/jcem.85.3.6459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10720072">Greenbaum et al. (2000)</a> noted that the presence of HLA haplotype DQA1*0102-DQB1*0602 is associated with protection from type 1 diabetes. The Diabetes Prevention Trial-type I has identified 100 islet cell antibody (ICA)-positive relatives with this protective haplotype, far exceeding the number of such subjects reported in other studies worldwide. Comparisons between ICA+ relatives with and without DQB1*0602 demonstrated no differences in gender or age; however, among racial groups, African American ICA+ relatives were more likely to carry this haplotype than others. The ICA+ DQB1*0602 individuals were less likely to have additional risk factors for diabetes (insulin autoantibody (IAA) positive or low first phase insulin release (FPIR)) than ICA+ relatives without DQB1*0602. However, 29% of the ICA+ DQB1*0602 relatives did have IAA or low FPIR. Hispanic ICA+ individuals with DQB1*0602 were more likely to be IAA positive or to have low FPIR than other racial groups. The authors conclude that the presence of ICA found in relatives suggests that whatever the mechanism that protects DQB1*0602 individuals from diabetes, it is likely to occur after the diabetes disease process has begun. In addition, they suggest that there may be different effects of DQB1*0602 between ethnic groups. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10720072" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#103" class="mim-tip-reference" title="Redondo, M. J., Kawasaki, E., Mulgrew, C. L., Noble, J. A., Erlich, H. A., Freed, B. M., Lie, B. A., Thorsby, E., Eisenbarth, G. S., Undlien, D. E., Ronningen, K. S. <strong>DR- and DQ-associated protection from type 1A diabetes: comparison of DRB1*1401 and DQA1*0102-DQB1*0602.</strong> J. Clin. Endocr. Metab. 85: 3793-3797, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11061540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11061540</a>] [<a href="https://doi.org/10.1210/jcem.85.10.6920" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11061540">Redondo et al. (2000)</a> used the transmission disequilibrium test to analyze haplotypes for association and linkage to diabetes within families from the Human Biological Data Interchange type I diabetes repository (1,371 subjects) and from the Norwegian Type 1 Diabetes Simplex Families study (2,441 subjects). DQA1*0102-DQB1*0602 was transmitted to 2 of 313 (0.6%) affected offspring (P less than 0.001, vs the expected 50% transmission). Protection was associated with the DQ alleles rather than DRB1*1501 in linkage disequilibrium with DQA1*0102-DQB1*0602: rare DRB1*1501 haplotypes without DQA1*0102-DQB1*0602 were transmitted to 5 of 11 affected offspring, whereas DQA1*0102-DQB1*0602 was transmitted to 2 of 313 affected offspring (P less than 0.0001). The authors concluded that both DR and DQ molecules (the DRB1*1401 and DQA1*0102-DQB1*0602 alleles) can provide protection from type IA diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11061540" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#74" class="mim-tip-reference" title="Li, H., Lindholm, E., Almgren, P., Gustafsson, A., Forsblom, C., Groop, L., Tuomi, T. <strong>Possible human leukocyte antigen-mediated genetic interaction between type 1 and type 2 diabetes.</strong> J. Clin. Endocr. Metab. 86: 574-582, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11158011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11158011</a>] [<a href="https://doi.org/10.1210/jcem.86.2.7170" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11158011">Li et al. (2001)</a> assessed the prevalence of families with both type 1 and type 2 diabetes in Finland and studied, in patients with type 2 diabetes, the association between a family history of type 1 diabetes, GAD antibodies (GADab), and type 1 diabetes-associated HLA-DQB1 genotypes. Further, in mixed type 1/type 2 diabetes families, they investigated whether sharing an HLA haplotype with a family member with type 1 diabetes influenced the manifestation of type 2 diabetes. Among 695 families with more than 1 patient with type 2 diabetes, 100 (14%) also had members with type 1 diabetes. Type 2 diabetic patients from the mixed families more often had GADab (18% vs 8%) and DQB1*0302/X genotype (25% vs 12%) than patients from families with only type 2 diabetes; however, they had a lower frequency of DQB1*02/0302 genotype compared with adult-onset type 1 patients (4% vs 27%). In the mixed families, the insulin response to oral glucose load was impaired in patients who had HLA class II risk haplotypes, either DR3(17)-DQA1*0501-DQB1*02 or DR4*0401/4-DQA1*0301-DQB1*0302, compared with patients without such haplotypes. This finding was independent of the presence of GADab. The authors concluded that type 1 and type 2 diabetes cluster in the same families. A shared genetic background with a patient with type 1 diabetes predisposes type 2 diabetic patients both to autoantibody positivity and, irrespective of antibody positivity, to impaired insulin secretion. Their findings also supported a possible genetic interaction between type 1 and type 2 diabetes mediated by the HLA locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11158011" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Linkage data implicating other disease susceptibility loci for type 1 diabetes are conflicting. This is likely due to (1) the limited power for detection of contributions of additional susceptibility loci, given the limited number of informative families available for study; (2) factors such as genetic heterogeneity between populations; and (3) potential gene-gene and gene-environment interactions. To circumvent some of these problems, the <a href="#40" class="mim-tip-reference" title="European Consortium for IDDM Genome Studies. <strong>A genomewide scan for type 1-diabetes susceptibility in Scandinavian families: identification of new loci with evidence of interactions.</strong> Am. J. Hum. Genet. 69: 1301-1313, 2001. Note: Erratum: Am. J. Hum. Genet. 70: 1075 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11598829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11598829</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11598829[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/324341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11598829">European Consortium for IDDM Genome Studies (2001)</a> conducted a genomewide linkage analysis for type 1 diabetes mellitus-susceptibility loci in 408 multiplex families from Scandinavia, a population expected to be homogeneous for genetic and environmental factors. In addition to verifying the HLA and INS susceptibility loci, the study confirmed the locus of IDDM15 (<a href="/entry/601666">601666</a>) on chromosome 6q21. Suggestive evidence of additional susceptibility loci was found on 2p, 5q, and 16p. For some loci, the support for linkage increased substantially when families were stratified on the basis of HLA or INS genotypes, with statistically significant heterogeneity between the stratified subgroups. These data support both the existence of non-HLA genes of significance for type 1 diabetes mellitus and the interaction between HLA and non-HLA loci in the determination of the type 1 diabetes mellitus phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11598829" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#47" class="mim-tip-reference" title="Gambelunghe, G., Ghaderi, M., Tortoioli, C., Falorni, A., Santeusanio, F., Brunetti, P., Sanjeevi, C. B., Falorni, A. on behalf of the Umbria Type 1 Diabetes Registry. <strong>Two distinct MICA gene markers discriminate major autoimmune diabetes types.</strong> J. Clin. Endocr. Metab. 86: 3754-3760, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11502807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11502807</a>] [<a href="https://doi.org/10.1210/jcem.86.8.7769" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11502807">Gambelunghe et al. (2001)</a> estimated the frequency of major histocompatibility complex class I chain-related A gene (MICA; <a href="/entry/600169">600169</a>) alleles and HLA-DRB1*03-DQA1*0501-DQB1*0201 and HLA-DRB1*04-DQA1*0301-DQB1*0302 in 195 type 1 diabetes mellitus subjects, in 80 latent autoimmune diabetes of the adult subjects, and in 158 healthy subjects from central Italy. The MICA5 allele was significantly associated with type 1 diabetes mellitus only in the group diagnosed before 25 years of age, and the odds ratio of the simultaneous presence of both the MICA5 allele and HLA-DRB1*03-DQA1*0501-DQB1*0201 and/or HLA-DRB1*04-DQA1*0301-DQB1*0302 was as high as 54 and higher than 388 when compared with double-negative individuals. Adult-onset type 1 diabetes mellitus (age at diagnosis greater than 25 years) and latent autoimmune diabetes of the adult were significantly associated with the MICA5.1 allele, which was not significantly increased among diabetic children. Only the combination of MICA5.1 and HLA-DRB1*03-DQA1*0501-DQB1*0201 and/or HLA-DRB1*04-DQA1*0301-DQB1*0302 conferred increased risk for adult-onset type 1 diabetes mellitus or for latent autoimmune diabetes of the adult. The authors concluded the existence of distinct genetic markers for childhood/young-onset IDDM and for adult-onset IDDM, namely the MICA5 and MICA5.1 alleles, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11502807" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#101" class="mim-tip-reference" title="Qu, H.-Q., Polychronakos, C. <strong>The effect of the MHC locus on autoantibodies in type 1 diabetes. (Letter)</strong> J. Med. Genet. 46: 469-471, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19429597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19429597</a>] [<a href="https://doi.org/10.1136/jmg.2009.066647" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19429597">Qu and Polychronakos (2009)</a> analyzed anti-IA-2 and anti-GAD65 autoantibody data from 2,282 type 1 diabetes patients from 1,117 multiplex families and found no association between anti-GAD65 (<a href="/entry/138275">138275</a>) autoantibodies and HLA. However, significant positive association was detected between anti-IA-2 (<a href="/entry/601773">601773</a>) autoantibodies and HLA-DRB1*0401, whereas negative association was detected with the DRB1*03-DQA1*0501-DQB1*0201 haplotype as well as with HLA-A*24, independent of the DRB1*03-DQA1*0501-DQB1*0201 haplotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19429597" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The <a href="#148" class="mim-tip-reference" title="Wellcome Trust Case Control Consortium. <strong>Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls.</strong> Nature 464: 713-720, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20360734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20360734</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20360734[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08979" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20360734">Wellcome Trust Case Control Consortium (2010)</a> undertook a large direct genomewide study of association between copy number variants (CNVs) and 8 common human diseases. Using a purpose-designed array, they typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated 50% of all common CNVs greater than 500 basepairs. The <a href="#148" class="mim-tip-reference" title="Wellcome Trust Case Control Consortium. <strong>Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls.</strong> Nature 464: 713-720, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20360734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20360734</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20360734[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08979" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20360734">Wellcome Trust Case Control Consortium (2010)</a> identified several biologic artifacts that led to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed 3 loci where CNVs were associated with disease: HLA for Crohn disease (<a href="/entry/266600">266600</a>), rheumatoid arthritis (RA; <a href="/entry/180300">180300</a>), and IDDM; IRGM (<a href="/entry/608282">608282</a>) for Crohn disease; and TSPAN8 (<a href="/entry/600769">600769</a>) for type 2 diabetes (<a href="/entry/125853">125853</a>). In each case the locus had previously been identified in SNP-based studies, reflecting the observation of The <a href="#148" class="mim-tip-reference" title="Wellcome Trust Case Control Consortium. <strong>Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls.</strong> Nature 464: 713-720, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20360734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20360734</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20360734[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08979" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20360734">Wellcome Trust Case Control Consortium (2010)</a> that most common CNVs that are well-typed on their array are well-tagged by SNPs and so have been indirectly explored through SNP studies. The <a href="#148" class="mim-tip-reference" title="Wellcome Trust Case Control Consortium. <strong>Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls.</strong> Nature 464: 713-720, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20360734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20360734</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20360734[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08979" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20360734">Wellcome Trust Case Control Consortium (2010)</a> concluded that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20360734" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#136" class="mim-tip-reference" title="Todd, J. A., Bell, J. I., McDevitt, H. O. <strong>HLA-DQ(beta) gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus.</strong> Nature 329: 599-604, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3309680/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3309680</a>] [<a href="https://doi.org/10.1038/329599a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3309680">Todd et al. (1987)</a> estimated that more than half of the inherited predisposition to IDDM maps to the region of the HLA class II genes on chromosome 6. Analysis of the DNA sequences from diabetics indicated that alleles of HLA-DQ(beta) determined both disease susceptibility and resistance. A non-asp at residue 57 of the beta-chain in particular confers susceptibility to IDDM and the autoimmune response against the insulin-producing islet cells. <a href="#81" class="mim-tip-reference" title="Morel, P. A., Dorman, J. S., Todd, J. A., McDevitt, H. O., Trucco, M. <strong>Aspartic acid at position 57 of the HLA-DQ beta chain protects against type I diabetes: a family study.</strong> Proc. Nat. Acad. Sci. 85: 8111-8115, 1988. Note: Erratum: Proc. Nat. Acad. Sci. 86: 1317 only, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3186714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3186714</a>] [<a href="https://doi.org/10.1073/pnas.85.21.8111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3186714">Morel et al. (1988)</a> found that HLA haplotypes carrying an asp in position 57 of the DQ-beta chain (<a href="/entry/146880">146880</a>) were significantly increased in frequency among nondiabetics, while non-asp57 haplotypes were significantly increased in frequency among diabetics. Ninety-six percent of the diabetic probands were homozygous non-asp/non-asp as compared to 19.5% of healthy, unrelated controls. This represented a relative risk of 107 for non-asp57 homozygous individuals. See critique by <a href="#66" class="mim-tip-reference" title="Klitz, W. <strong>Inheritance of insulin-dependent diabetes. (Letter)</strong> Nature 333: 402-403, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3374583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3374583</a>] [<a href="https://doi.org/10.1038/333402c0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3374583">Klitz (1988)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3186714+3374583+3309680" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#64" class="mim-tip-reference" title="Khalil, I., d'Auriol, L., Gobet, M., Morin, L., Lepage, V., Deschamps, I., Park, M. S., Degos, L., Galibert, F., Hors, J. <strong>A combination of HLA-DQ-beta asp57-negative and HLA DQ-alpha arg52 confers susceptibility to insulin-dependent diabetes mellitus.</strong> J. Clin. Invest. 85: 1315-1319, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2318983/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2318983</a>] [<a href="https://doi.org/10.1172/JCI114569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2318983">Khalil et al. (1990)</a> presented evidence suggesting that asp57-negative DQ-beta as well as arg52-positive DQ-alpha chains are important to susceptibility to IDDM. Presumably, the modulation of susceptibility operates via the presentation of viral-antigenic peptide and/or autoantigen. I-Ag7, the only class II allele expressed by the nonobese diabetic mouse, lacks asp57. <a href="#26" class="mim-tip-reference" title="Corper, A. L., Stratmann, T., Apostolopoulos, V., Scott, C. A., Garcia, K. C., Kang, A. S., Wilson, I. A., Teyton, L. <strong>A structural framework for deciphering the link between I-AG7 and autoimmune diabetes.</strong> Science 288: 505-511, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10775108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10775108</a>] [<a href="https://doi.org/10.1126/science.288.5465.505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10775108">Corper et al. (2000)</a> determined the crystal structure of the I-Ag7 molecule at 2.6-angstrom resolution as a complex with a high-affinity peptide from the autoantigen glutamic acid decarboxylase (GAD) 65 (<a href="/entry/138275">138275</a>). I-Ag7 has a substantially wider peptide-binding groove around beta-57, which accounts for distinct peptide preferences compared with other MHC class II alleles. Loss of asp-beta-57 leads to an oxyanion hole in I-Ag7 that can be filled by peptide carboxyl residues or, perhaps, through interaction with the T-cell receptor (see <a href="/entry/186830">186830</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10775108+2318983" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#83" class="mim-tip-reference" title="Nakanishi, K., Kobayashi, T., Murase, T., Naruse, T., Nose, Y., Inoko, H. <strong>Human leukocyte antigen-A24 and -DQA1*0301 in Japanese insulin-dependent diabetes mellitus: independent contributions to susceptibility to the disease and additive contributions to acceleration of beta-cell destruction.</strong> J. Clin. Endocr. Metab. 84: 3721-3725, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10523020/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10523020</a>] [<a href="https://doi.org/10.1210/jcem.84.10.6045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10523020">Nakanishi et al. (1999)</a> sought to identify IDDM-susceptible HLA antigens in IDDM patients who did not have the HLA-DQA1*0301 allele and to correlate the relationship of these HLA antigens to the degree of beta-cell destruction. In 139 Japanese IDDM patients and 158 normal controls, they typed HLA-A, -C, -B, -DR, and -DQ antigens. Serum C-peptide immunoreactivity response (delta-CPR) to a 100-g oral glucose load of 0.033 nmol/L or less was regarded as complete beta-cell destruction. All 14 patients without HLA-DQA1*0301 had HLA-A24, whereas only 35 of 58 (60.3%) normal controls without HLA-DQA1*0301 and only 72 of 125 (57.6%) IDDM patients with HLA-DQA1*0301 had this antigen (Pc of 0.0256 and 0.0080, respectively). Delta-CPR in IDDM patients with both HLA-DQA1*0301 and HLA-A24 was lower than in IDDM patients with HLA-DQA1*0301 only and in IDDM patients with HLA-A24 only. The authors concluded that both HLA-DQA1*0301 and HLA-A24 contribute susceptibility to IDDM independently and accelerate beta-cell destruction in an additive manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10523020" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Donner, H., Tonjes, R. R., Van der Auwera, B., Siegmund, T., Braun, J., Weets, I., Belgian Diabetes Registry, Herwig, J., Kurth, R., Usadel, K. H., Badenhoop, K. <strong>The presence or absence of a retroviral long terminal repeat influences the genetic risk for type 1 diabetes conferred by human leukocyte antigen DQ haplotypes.</strong> J. Clin. Endocr. Metab. 84: 1404-1408, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10199786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10199786</a>] [<a href="https://doi.org/10.1210/jcem.84.4.5638" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10199786">Donner et al. (1999)</a> analyzed the presence of a solitary human endogenous retrovirus-K (HERV-K) long terminal repeat (LTR) in the HLA-DQ region (DQ-LTR3) and its linkage to DRB1, DQA1, and DQB1 haplotypes derived from 246 German and Belgian families with a patient suffering from IDDM. Segregation analysis of 984 HLA-DQA1/B1 haplotypes showed that DQ-LTR3 is linked to distinct DQA1 and DQB1 haplotypes but is absent in others. The presence of DQ-LTR3 on HLA-DQB1*0302 haplotypes was preferentially transmitted to patients from heterozygous parents (82%; P less than 10-6), in contrast to only 2 of 7 DQB1*0302 haplotypes without DQ-LTR3. Also, the extended HLA-DRB1*0401, DQB1*0302 DQ-LTR3-positive haplotypes were preferentially transmitted (84%; P less than 10-6) compared with 1 of 6 DR-DQ-matched DQ-LTR3-negative haplotypes. DQ-LTR3 is missing on most DQB1*0201 haplotypes, and those LTR3-negative haplotypes were also preferentially transmitted to patients (80%; P less than 10-6), whereas DQB1*0201 DQ-LTR3-positive haplotypes were less often transmitted to patients (36%). The authors concluded that the presence of DQ-LTR3 on HLA-DQB1*0302 and its absence on DQB1*0201 haplotypes are independent genetic risk markers for IDDM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10199786" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#99" class="mim-tip-reference" title="Pugliese, A., Kawasaki, E., Zeller, M., Yu, L., Babu, S., Solimena, M., Moraes, C. T., Pietropaolo, M., Friday, R. P., Trucco, M., Ricordi, C., Allen, M., Noble, J. A., Erlich, H. A., Eisenbarth, G. S. <strong>Sequence analysis of the diabetes-protective human leukocyte antigen-DQB1*0602 allele in unaffected, islet cell antibody-positive first degree relatives and in rare patients with type 1 diabetes.</strong> J. Clin. Endocr. Metab. 84: 1722-1728, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10323407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10323407</a>] [<a href="https://doi.org/10.1210/jcem.84.5.5684" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10323407">Pugliese et al. (1999)</a> sequenced the DQB1*0602 and DQA1*0102 alleles in 8 ICA/DQB1*0602-positive relatives and in 6 rare patients with type 1 diabetes and DQB1*0602. They found that all relatives and patients carry the known DQB1*0602 and DQA1*0102 sequences, and none of them had the mtDNA 3243A-G mutation (<a href="/entry/590050#0001">590050.0001</a>) associated with late-onset diabetes in ICA-positive individuals. Because they did not find diabetes in ICA/DQB1*0602-positive relatives, the authors concluded that the development of diabetes in individuals with DQB1*0602 remains very unlikely, even in the presence of ICA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10323407" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Cordell, H. J., Todd, J. A., Bennett, S. T., Kawaguchi, Y., Farrall, M. <strong>Two-locus maximum lod score analysis of a multifactorial trait: joint consideration of IDDM2 and IDDM4 with IDDM1 in type I diabetes.</strong> Am. J. Hum. Genet. 57: 920-934, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7573054/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7573054</a>]" pmid="7573054">Cordell et al. (1995)</a> applied to insulin-dependent diabetes mellitus an extension of the maximum lod score method of <a href="#108" class="mim-tip-reference" title="Risch, N. <strong>Linkage strategies for genetically complex traits. I. Multilocus models.</strong> Am. J. Hum. Genet. 46: 222-228, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2301392/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2301392</a>]" pmid="2301392">Risch (1990)</a>, which allowed the simultaneous detection and modeling of 2 unlinked disease loci. The method was applied to affected sib pair data, and the joint effects of IDDM1 (HLA) and IDDM2, the INS VNTR, and IDDM1 and IDDM4 (FGF3-linked) were assessed. In the presence of genetic heterogeneity, there seemed to be a significant advantage in analyzing more than 1 locus simultaneously. <a href="#24" class="mim-tip-reference" title="Cordell, H. J., Todd, J. A., Bennett, S. T., Kawaguchi, Y., Farrall, M. <strong>Two-locus maximum lod score analysis of a multifactorial trait: joint consideration of IDDM2 and IDDM4 with IDDM1 in type I diabetes.</strong> Am. J. Hum. Genet. 57: 920-934, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7573054/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7573054</a>]" pmid="7573054">Cordell et al. (1995)</a> stated that the effects at IDDM1 and IDDM2 were well described by a multiplicative genetic model, while those at IDDM1 and IDDM4 followed a heterogeneity model. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7573054+2301392" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Cucca, F., Lampis, R., Congia, M., Angius, E., Nutland, S., Bain, S. C., Barnett, A. H., Todd, J. A. <strong>A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins.</strong> Hum. Molec. Genet. 10: 2025-2037, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11590120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11590120</a>] [<a href="https://doi.org/10.1093/hmg/10.19.2025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11590120">Cucca et al. (2001)</a> predicted the protein structure of HLA-DQ by using the published crystal structures of different allotypes of the murine ortholog of DQ, IA. There were marked similarities both within and across species between type 1 diabetes protective class II molecules. Likewise, the type 1 diabetes predisposing molecules DR and murine IE showed conserved similarities that contrasted with the shared patterns observed between the protective molecules. There was also inter-isotypic conservation between protective DQ, IA allotypes, and protective DR4 subtypes. The authors proposed a model for a joint action of the class II peptide-binding pockets P1, P4, and P9 in disease susceptibility and resistance with a main role for P9 in DQ/IA and for P1 and P4 in DR/IE. They suggested shared epitope(s) in the target autoantigen(s) and common pathways in human and murine type 1 diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11590120" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#69" class="mim-tip-reference" title="Kristiansen, O. P., Nolsoe, R. L., Larsen, L., Gjesing, A. M. P., Johannesen, J., Larsen, Z. M., Lykkesfeldt, A. E., Karlsen, A. E., Pociot, F., Mandrup-Poulsen, T. <strong>Association of a functional 17-beta-estradiol sensitive IL6-174G/C promoter polymorphism with early-onset type 1 diabetes in females.</strong> Hum. Molec. Genet. 12: 1101-1110, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12719374/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12719374</a>] [<a href="https://doi.org/10.1093/hmg/ddg132" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12719374">Kristiansen et al. (2003)</a> demonstrated that the -174C variant of the -174G/C SNP in the IL6 gene (<a href="/entry/147620#0001">147620.0001</a>) was significantly associated with IDDM in Danish females, but not in males, and that the association was not caused by preferential transmission distortion in females. Using reporter assay studies, they also demonstrated evidence suggesting that the repressed PMA-stimulated activity of the -174G variant was reverted by 17-beta-estradiol (E2), whereas the stimulated activity of the -174C variant was E2 insensitive and higher than the stimulated activity of the -174G variant in the absence of E2. <a href="#69" class="mim-tip-reference" title="Kristiansen, O. P., Nolsoe, R. L., Larsen, L., Gjesing, A. M. P., Johannesen, J., Larsen, Z. M., Lykkesfeldt, A. E., Karlsen, A. E., Pociot, F., Mandrup-Poulsen, T. <strong>Association of a functional 17-beta-estradiol sensitive IL6-174G/C promoter polymorphism with early-onset type 1 diabetes in females.</strong> Hum. Molec. Genet. 12: 1101-1110, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12719374/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12719374</a>] [<a href="https://doi.org/10.1093/hmg/ddg132" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12719374">Kristiansen et al. (2003)</a> concluded that higher IL6 promoter activity may confer risk to IDDM in very young females and that this risk may be negated with increasing age, possibly by the increasing E2 levels in puberty. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12719374" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Bottini, N., Musumeci, L., Alonso, A., Rahmouni, S., Nika, K., Rostamkhani, M., MacMurray, J., Meloni, G. F., Lucarelli, P., Pellecchia, M., Eisenbarth, G. S., Comings, D., Mustelin, T. <strong>A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes.</strong> Nature Genet. 36: 337-338, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15004560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15004560</a>] [<a href="https://doi.org/10.1038/ng1323" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15004560">Bottini et al. (2004)</a> demonstrated association of a missense SNP in the PTPN22 gene (R620W; <a href="/entry/600716#0001">600716.0001</a>) with type 1 diabetes. <a href="#62" class="mim-tip-reference" title="Kawasaki, E., Awata, T., Ikegami, H., Kobayashi, T., Maruyama, T., Nakanishi, K., Shimada, A., Uga, M., Kurihara, S., Kawabata, Y., Tanaka, S., Kanazawa, Y., Lee, I., Eguchi, K., Japanese Study Group on Type 1 Diabetes Genetics. <strong>Systematic search for single nucleotide polymorphisms in a lymphoid tyrosine phosphatase gene (PTPN22): association between a promoter polymorphism and type 1 diabetes in Asian populations.</strong> Am. J. Med. Genet. 140A: 586-593, 2006. Note: Erratum: Am. J. Med. Genet. 143A: 18212-18213, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16470599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16470599</a>] [<a href="https://doi.org/10.1002/ajmg.a.31124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16470599">Kawasaki et al. (2006)</a> identified a promoter SNP in the PTPN22 gene (<a href="/entry/600716#0002">600716.0002</a>) that associated with type 1 diabetes in Japanese and Korean IDDM patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15004560+16470599" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#131" class="mim-tip-reference" title="Tessier, M.-C., Qu, H.-Q., Frechette, R., Bacot, F., Grabs, R., Taback, S. P., Lawson, M. L., Kirsch, S. E., Hudson, T. J., Polychronakos, C. <strong>Type 1 diabetes and the OAS gene cluster: association with splicing polymorphism or haplotype?</strong> J. Med. Genet. 43: 129-132, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16014697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16014697</a>] [<a href="https://doi.org/10.1136/jmg.2005.035212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16014697">Tessier et al. (2006)</a> reported association of type 1 diabetes with 2 SNPs in the OAS1 gene (<a href="/entry/164350#0001">164350.0001</a>, <a href="/entry/164350#0002">164350.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16014697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#121" class="mim-tip-reference" title="Smyth, D. J., Plagnol, V., Walker, N. M., Cooper, J. D., Downes, K., Yang, J. H. M., Howson, J. M. M., Stevens, H., McManus, R., Wijmenga, C., Heap, G. A., Dubois, P. C., Clayton, D. G., Hunt, K. A., van Heel, D. A., Todd, J. A. <strong>Shared and distinct genetic variants in type 1 diabetes and celiac disease.</strong> New Eng. J. Med. 359: 2767-2777, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19073967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19073967</a>] [<a href="https://doi.org/10.1056/NEJMoa0807917" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19073967">Smyth et al. (2008)</a> identified a significant association between an insertion-deletion variant in the CCR5 gene on chromosome 3p21 (<a href="/entry/601373#0001">601373.0001</a>) and a reduced risk for type 1 diabetes (IDDM22; <a href="/entry/612522">612522</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19073967" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Concannon, P., Rich, S. S., Nepom, G. T. <strong>Genetics of type 1A diabetes.</strong> New Eng. J. Med. 360: 1646-1654, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19369670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19369670</a>] [<a href="https://doi.org/10.1056/NEJMra0808284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19369670">Concannon et al. (2009)</a> reviewed the genetics of type 1A (immune-mediated) diabetes, noting that genes within the HLA region, predominantly those that encode antigen-presenting molecules, confer the greatest part of the genetic risk for type 1A diabetes. The authors concluded that the existence of other loci with individual effects on risk of a similar magnitude is very unlikely, and suggested that the remaining non-HLA loci will make only modest individual contributions to risk, with odds ratios of 1.3 or less. <a href="#21" class="mim-tip-reference" title="Concannon, P., Rich, S. S., Nepom, G. T. <strong>Genetics of type 1A diabetes.</strong> New Eng. J. Med. 360: 1646-1654, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19369670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19369670</a>] [<a href="https://doi.org/10.1056/NEJMra0808284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19369670">Concannon et al. (2009)</a> noted that a majority of the other loci appear to exert their effects in the immune system, particularly on T cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19369670" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#153" class="mim-tip-reference" title="Zalloua, P. A., Azar, S. T., Delepine, M., Makhoul, N. J., Blanc, H., Sanyoura, M., Lavergne, A., Stankov, K., Lemainque, A., Baz, P., Julier, C. <strong>WFS1 mutations are frequent monogenic causes of juvenile-onset diabetes mellitus in Lebanon.</strong> Hum. Molec. Genet. 17: 4012-4021, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18806274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18806274</a>] [<a href="https://doi.org/10.1093/hmg/ddn304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18806274">Zalloua et al. (2008)</a> identified homozygous or compound heterozygous mutations in the WFS1 gene (see, e.g., <a href="/entry/606201#0024">606201.0024</a>) in 22 (5.5%) of 399 Lebanese probands ascertained with juvenile-onset insulin-dependent diabetes, of whom 17 had Wolfram syndrome (WFS1; <a href="/entry/222300">222300</a>) and 5 had nonsyndromic nonautoimmune diabetes mellitus. There were 2 additional probands who were given an initial diagnosis of nonsyndromic DM that was revised to WFS when they developed optic atrophy during the course of the study, and <a href="#153" class="mim-tip-reference" title="Zalloua, P. A., Azar, S. T., Delepine, M., Makhoul, N. J., Blanc, H., Sanyoura, M., Lavergne, A., Stankov, K., Lemainque, A., Baz, P., Julier, C. <strong>WFS1 mutations are frequent monogenic causes of juvenile-onset diabetes mellitus in Lebanon.</strong> Hum. Molec. Genet. 17: 4012-4021, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18806274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18806274</a>] [<a href="https://doi.org/10.1093/hmg/ddn304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18806274">Zalloua et al. (2008)</a> noted that longer follow-up of the nonsyndromic DM patients or a specific study of WFS adult patient populations would be needed to determine whether a subset of the WFS1-mutated nonsyndromic DM patients are exempted from extrapancreatic manifestations during their lifetime. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18806274" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#116" class="mim-tip-reference" title="Santiago, J. L., Alizadeh, B. Z., Martinez, A., Espino, L., de la Calle, H., Fernandez-Arquero, M., Figueredo, M. A., de la Concha, E. G., Roep, B. O., Koeleman, B. P. C., Urcelay, E. <strong>Study of the association between the CAPSL-IL7R locus and type 1 diabetes.</strong> Diabetologia 51: 1653-1658, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18563381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18563381</a>] [<a href="https://doi.org/10.1007/s00125-008-1070-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18563381">Santiago et al. (2008)</a> genotyped the CAPSL (<a href="/entry/618799">618799</a>) SNPs <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1445898;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1445898</a> and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1010601;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1010601</a> and 3 SNPs in the IL7R gene (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs6891932;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs6891932</a>, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs987106;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs987106</a>, and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3194051;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3194051</a>) in 301 unrelated Spanish type 1 diabetes patients and 646 healthy controls, and observed a trend towards a protective effect with the CAPSL SNP <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1445898;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1445898</a>. A similar trend for CAPSL <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1445898;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1445898</a> was observed in 429 Dutch patients with type 1 diabetes compared to 720 healthy controls, and pooling the cohorts yielded a statistically significant difference (p = 0.005). The authors concluded that the CAPSL-IL7R locus is a protective region, but stated that they could not elucidate whether the protective gene was CAPSL, IL7R, or both. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18563381" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The diagnosis of type 1 diabetes is made on the basis of hyperglycemia with relative insulin deficiency with, or in the early stages without, ketosis in the absence of medications or conditions known to promote hyperglycemia.</p><p>In a study of an unselected population of 755 sibs of children with IDDM, <a href="#70" class="mim-tip-reference" title="Kulmala, P., Savola, K., Petersen, J. S., Vahasalo, P., Karjalainen, J., Lopponen, T., Dyrberg, T., Akerblom, H. K., Knip, M., Childhood Diabetes in Finland Study Group. <strong>Prediction of insulin-dependent diabetes mellitus in siblings of children with diabetes: a population-based study.</strong> J. Clin. Invest. 101: 327-336, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9435304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9435304</a>] [<a href="https://doi.org/10.1172/JCI119879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9435304">Kulmala et al. (1998)</a> evaluated the predictive value of islet cell antibodies, antibodies to the IA-2 protein, antibodies to the 65-kD isoform of GADA, insulin autoantibodies, and combinations of these markers. Within 7.7 years of the initial sample taken at or close to the diagnosis in the index case, 32 sibs progressed to IDDM. The positive predictive values of the 4 antibodies mentioned were 43%, 55%, 42%, and 29%, and their sensitivities 81%, 69%, 69%, and 25%, respectively. The final conclusion made by <a href="#70" class="mim-tip-reference" title="Kulmala, P., Savola, K., Petersen, J. S., Vahasalo, P., Karjalainen, J., Lopponen, T., Dyrberg, T., Akerblom, H. K., Knip, M., Childhood Diabetes in Finland Study Group. <strong>Prediction of insulin-dependent diabetes mellitus in siblings of children with diabetes: a population-based study.</strong> J. Clin. Invest. 101: 327-336, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9435304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9435304</a>] [<a href="https://doi.org/10.1172/JCI119879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9435304">Kulmala et al. (1998)</a> was that accurate assessment of the risk for IDDM in sibs is complicated, as not even all those with 4 antibody specificities contract the disease, and some with only 1 or no antibodies initially will progress to IDDM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9435304" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#65" class="mim-tip-reference" title="Kimpimaki, T., Kulmala, P., Savola, K., Vahasalo, P., Reijonen, H., Ilonen, J., Akerblom, H. K., Knip, M., Childhood Diabetes in Finland Study Group. <strong>Disease-associated autoantibodies as surrogate markers of type 1 diabetes in young children at increased genetic risk.</strong> J. Clin. Endocr. Metab. 85: 1126-1132, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10720050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10720050</a>] [<a href="https://doi.org/10.1210/jcem.85.3.6466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10720050">Kimpimaki et al. (2000)</a> evaluated the emergence of diabetes-associated autoantibodies in young children and assessed whether such antibodies could be used as surrogate markers of type 1 diabetes in young subjects at increased genetic risk. They studied 180 initially unaffected sibs (92 boys and 88 girls) of children with newly diagnosed type 1 diabetes. All sibs were younger than 6 years of age at the initial sampling, and they were monitored for the emergence of islet cell antibodies (ICA), insulin autoantibodies (IAA), glutamate decarboxylase antibodies (GADA), and IA-2 antibodies (IA-2A) up to the age of 6 years and for progression to clinical type 1 diabetes up to the age of 10 years. Twenty-two sibs (12.2%) tested positive for ICA in their first antibody-positive sample before the age of 6 years, 13 (7.2%) tested positive for IAA, 15 (8.3%) tested positive for GADA, and 14 (7.8%) tested positive for IA-2A. There were 16 sibs (8.9%) who had 1 detectable autoantibody, 5 (2.8%) who had 2, and 12 (6.7%) who had 3 or more. These observations suggested to <a href="#65" class="mim-tip-reference" title="Kimpimaki, T., Kulmala, P., Savola, K., Vahasalo, P., Reijonen, H., Ilonen, J., Akerblom, H. K., Knip, M., Childhood Diabetes in Finland Study Group. <strong>Disease-associated autoantibodies as surrogate markers of type 1 diabetes in young children at increased genetic risk.</strong> J. Clin. Endocr. Metab. 85: 1126-1132, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10720050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10720050</a>] [<a href="https://doi.org/10.1210/jcem.85.3.6466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10720050">Kimpimaki et al. (2000)</a> that disease-associated autoantibodies could be used as surrogate markers of clinical type 1 diabetes in primary prevention trials targeting young subjects with increased genetic disease susceptibility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10720050" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#150" class="mim-tip-reference" title="Wenzlau, J. M., Juhl, K., Yu, L., Moua, O., Sarkar, S. A., Gottlieb, P., Rewers, M., Eisenbarth, G. S., Jensen, J., Davidson, H. W., Hutton, J. C. <strong>The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes.</strong> Proc. Nat. Acad. Sci. 104: 17040-17045, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17942684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17942684</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17942684[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0705894104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17942684">Wenzlau et al. (2007)</a> identified type 1 diabetes autoantigen candidates from microarray expression profiling of human and rodent pancreas and islet cells, then screened the candidates with radioimmunoprecipitation assays using new-onset type 1 diabetes and prediabetic sera. The zinc transporter SLC30A8 (<a href="/entry/611145">611145</a>) was targeted by autoantibodies in 60 to 80% of new-onset type 1 diabetes compared with less than 2% of controls, less than 3% of patients with type 2 diabetes, and up to 30% of patients with other autoimmune disorders with a type 1 diabetes association. SLC30A8 antibodies were found in 26% of type 1 diabetics classified as autoantibody-negative on the basis of existing markers; the combined measurement of antibodies to SLC30A8, GADA, IA2, and insulin raised autoimmunity detection rates to 98% at disease onset. <a href="#150" class="mim-tip-reference" title="Wenzlau, J. M., Juhl, K., Yu, L., Moua, O., Sarkar, S. A., Gottlieb, P., Rewers, M., Eisenbarth, G. S., Jensen, J., Davidson, H. W., Hutton, J. C. <strong>The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes.</strong> Proc. Nat. Acad. Sci. 104: 17040-17045, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17942684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17942684</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17942684[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0705894104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17942684">Wenzlau et al. (2007)</a> concluded that SLC30A8 is a major autoantigen in type 1 diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17942684" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Clinical management of T1D requires use of dietary alterations and insulin therapy to maintain blood glucose levels within accepted range.</p><p><a href="#72" class="mim-tip-reference" title="Lee, H. C., Kim, S.-J., Kim, K.-S., Shin, H.-C., Yoon, J.-W. <strong>Remission in models of type 1 diabetes by gene therapy using a single-chain insulin analogue.</strong> Nature 408: 483-488, 2000. Note: Retraction: Nature 458: 660 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11100731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11100731</a>] [<a href="https://doi.org/10.1038/35044106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11100731">Lee et al. (2000)</a> reported that a single-chain insulin analog (SIA) produced from the gene construct recombinant adeno-associated virus (AAV)-L-type pyruvate kinase (LPK)-SIA caused remission of diabetes in streptozotocin-induced diabetic rats and autoimmune diabetic mice for up to 8 months without any apparent side effects. Three of the authors retracted the paper in 2009 on the grounds that they had not been able to reproduce the results. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11100731" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Cheung, A. T., Dayanandan, B., Lewis, J. T., Korbutt, G. S., Rajotte, R. V., Bryer-Ash, M., Boylan, M. O., Wolfe, M. M., Kieffer, T. J. <strong>Glucose-dependent insulin release from genetically engineered K cells.</strong> Science 290: 1959-1962, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11110661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11110661</a>] [<a href="https://doi.org/10.1126/science.290.5498.1959" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11110661">Cheung et al. (2000)</a> found that gut K cells could be induced to produce human insulin by providing the cells with the human insulin gene linked to the 5-prime regulatory region of the gene encoding glucose-dependent insulinotropic polypeptide (GIP; <a href="/entry/137240">137240</a>). Mice expressing this transgene produced human insulin specifically in gut K cells. This insulin protected the mice from developing diabetes and maintained glucose tolerance after destruction of the native insulin-producing beta cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11110661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#46" class="mim-tip-reference" title="Furuyama, K., Chera, S., van Gurp, L., Oropeza, D., Ghila, L., Damond, N., Vethe, H., Paulo, J. A., Joosten, A. M., Berney, T., Bosco, D., Dorrell, C., Grompe, M., Raeder, H., Roep, B. O., Thorel, F., Herrera, P. L. <strong>Diabetes relief in mice by glucose-sensing insulin-secreting human alpha-cells.</strong> Nature 567: 43-48, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30760930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30760930</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30760930[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-019-0942-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30760930">Furuyama et al. (2019)</a> showed that islet non-beta cells, namely alpha-cells and pancreatic polypeptide (PPY; <a href="/entry/167780">167780</a>)-producing gamma cells, obtained from deceased nondiabetic or diabetic human donors, could be lineage-traced and reprogrammed by the transcription factors PDX1 (<a href="/entry/600733">600733</a>) and MAFA (<a href="/entry/610303">610303</a>) to produce and secrete insulin in response to glucose. When transplanted into diabetic mice, converted human alpha cells reversed diabetes and continued to produce insulin even after 6 months. Deep transcriptomic and proteomic characterization found that insulin-producing alpha cells maintained expression of alpha-cell markers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30760930" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>IDDM occurs about 20 times more frequently among children in the United States than among those in China. <a href="#4" class="mim-tip-reference" title="Bao, M.-Z., Wang, J.-X., Dorman, J. S., Trucco, M. <strong>HLA-DQ-beta non-asp-57 allele and incidence of diabetes in China and the USA. (Letter)</strong> Lancet 334: 497-498, 1989. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2570199/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2570199</a>] [<a href="https://doi.org/10.1016/s0140-6736(89)92102-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2570199">Bao et al. (1989)</a> examined the question of whether this was due to a difference in the frequency of the allele leading to aspartic acid in position 57 of the HLA-DQ-beta chain. The presence of asp57 (or A) seems to protect against IDDM, while a noncharged amino acid in the same position (NA) is associated with increased susceptibility. Among probands in the IDDM registries in Allegheny County, Pa., 96% were homozygous NA, 4% were heterozygous, and none was homozygous A. In studies of 18 Chinese IDDM patients and 25 unrelated healthy Chinese controls, <a href="#4" class="mim-tip-reference" title="Bao, M.-Z., Wang, J.-X., Dorman, J. S., Trucco, M. <strong>HLA-DQ-beta non-asp-57 allele and incidence of diabetes in China and the USA. (Letter)</strong> Lancet 334: 497-498, 1989. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2570199/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2570199</a>] [<a href="https://doi.org/10.1016/s0140-6736(89)92102-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2570199">Bao et al. (1989)</a> found that only 1 patient was homozygous NA and 13 were heterozygous, while among the 25 Chinese controls, 23 were homozygous A. The large proportion of homozygous A persons in the Chinese population is consistent with the low incidence of IDDM in China. The association between NA and IDDM may be strong in both populations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2570199" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Dorman, J. S., LaPorte, R. E., Stone, R. A., Trucco, M. <strong>Worldwide differences in the incidence of type I diabetes are associated with amino acid variation at position 57 of the HLA-DQ beta-chain.</strong> Proc. Nat. Acad. Sci. 87: 7370-7374, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2217170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2217170</a>] [<a href="https://doi.org/10.1073/pnas.87.19.7370" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2217170">Dorman et al. (1990)</a> hypothesized that the 30-fold difference in IDDM incidence across racial groups and countries is related to variability in the frequency of NA alleles. To test the hypothesis, they evaluated diabetic and nondiabetic persons in 5 populations, with risks that were low, moderate, and high. NA alleles were significantly associated with IDDM in all areas, with population-specific odds ratios for NA homozygotes relative to A homozygotes ranging from 14 to 111. <a href="#37" class="mim-tip-reference" title="Dorman, J. S., LaPorte, R. E., Stone, R. A., Trucco, M. <strong>Worldwide differences in the incidence of type I diabetes are associated with amino acid variation at position 57 of the HLA-DQ beta-chain.</strong> Proc. Nat. Acad. Sci. 87: 7370-7374, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2217170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2217170</a>] [<a href="https://doi.org/10.1073/pnas.87.19.7370" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2217170">Dorman et al. (1990)</a> used estimated genotype-specific incidence rates for Allegheny County, Pa., Caucasians to predict the overall incidence rates in the remaining populations. These predictions fell within the 95% confidence limits of the actual rates established from incidence registries. Results were considered consistent with the hypothesis that population variation in the distribution of NA alleles explains much of the geographic variation in IDDM incidence. <a href="#22" class="mim-tip-reference" title="Concannon, P., Wright, J. A., Wright, L. G., Sylvester, D. R., Spielman, R. S. <strong>T-cell receptor genes and insulin-dependent diabetes mellitus (IDDM): no evidence for linkage from affected sib pairs.</strong> Am. J. Hum. Genet. 47: 45-52, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1971998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1971998</a>]" pmid="1971998">Concannon et al. (1990)</a> excluded close linkage of a gene making a major contribution to susceptibility to IDDM and the genes for 2 T-cell receptors, TCRA (see <a href="/entry/186880">186880</a>) and TCRB (see <a href="/entry/186930">186930</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1971998+2217170" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a Japanese study, <a href="#59" class="mim-tip-reference" title="Imagawa, A., Hanafusa, T., Miyagawa, J., Matsuzawa, Y. <strong>A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies.</strong> New Eng. J. Med. 342: 301-307, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10655528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10655528</a>] [<a href="https://doi.org/10.1056/NEJM200002033420501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10655528">Imagawa et al. (2000)</a> described what appeared to be a novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. <a href="#73" class="mim-tip-reference" title="Lernmark, A. <strong>Rapid-onset type 1 diabetes with pancreatic exocrine dysfunction. (Letter)</strong> New Eng. J. Med. 342: 344-345, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10655534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10655534</a>] [<a href="https://doi.org/10.1056/NEJM200002033420508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10655534">Lernmark (2000)</a> argued that, despite the unusual features, these patients had autoimmune type 1 diabetes. Since the patients described by <a href="#59" class="mim-tip-reference" title="Imagawa, A., Hanafusa, T., Miyagawa, J., Matsuzawa, Y. <strong>A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies.</strong> New Eng. J. Med. 342: 301-307, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10655528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10655528</a>] [<a href="https://doi.org/10.1056/NEJM200002033420501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10655528">Imagawa et al. (2000)</a> had features of genetic susceptibility to autoimmune type 1 diabetes, <a href="#73" class="mim-tip-reference" title="Lernmark, A. <strong>Rapid-onset type 1 diabetes with pancreatic exocrine dysfunction. (Letter)</strong> New Eng. J. Med. 342: 344-345, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10655534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10655534</a>] [<a href="https://doi.org/10.1056/NEJM200002033420508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10655534">Lernmark (2000)</a> found it tempting to speculate that diabetes resulted from accelerated beta-cell destruction due to some environmental factor that had such a rapid effect that the autoimmune response characteristic of autoimmune type 1 diabetes was precluded. Along the same lines, <a href="#57" class="mim-tip-reference" title="Honeyman, M. C., Coulson, B. S., Harrison, L. C. <strong>A novel subtype of type 1 diabetes mellitus. (Letter)</strong> New Eng. J. Med. 342: 1835 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10866554/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10866554</a>] [<a href="https://doi.org/10.1056/NEJM200006153422413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10866554">Honeyman et al. (2000)</a> suggested that rotavirus, which is not infectious until it is activated by trypsin (a product of the exocrine pancreas that can infect islets in tissue culture), may have been a cause of clinically silent pancreatic infection in the patients reported by <a href="#59" class="mim-tip-reference" title="Imagawa, A., Hanafusa, T., Miyagawa, J., Matsuzawa, Y. <strong>A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies.</strong> New Eng. J. Med. 342: 301-307, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10655528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10655528</a>] [<a href="https://doi.org/10.1056/NEJM200002033420501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10655528">Imagawa et al. (2000)</a> and may have led to T cell-mediated loss of beta cells before islet-cell antibodies could develop. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10655528+10655534+10866554" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The incidence of IDDM in Korea is less than one-tenth of that in the United States, and it has been suggested that HLA alleles of Asian patients associated with diabetes differ from those of Caucasians. <a href="#95" class="mim-tip-reference" title="Park, Y., She, J.-X., Wang, C. Y., Lee, H., Babu, S., Erlich, H. A., Noble, J. A., Eisenbarth, G. S. <strong>Common susceptibility and transmission pattern of human leukocyte antigen DRB1-DQB1 haplotypes to Korean and Caucasian patients with type 1 diabetes.</strong> J. Clin. Endocr. Metab. 85: 4538-4542, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11134105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11134105</a>] [<a href="https://doi.org/10.1210/jcem.85.12.7024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11134105">Park et al. (2000)</a> analyzed the common susceptibility and transmission pattern of a series of HLA DRB1-DQB1 haplotypes to Korean and Caucasian patients with IDDM. They performed HLA DR and DQ typing of 158 IDDM patients in a case control study, 140 nondiabetic subjects from the same geographic area, 49 simplex families from Seoul, and 283 families from the Human Biological Data Interchange. Although the haplotype frequencies in the 2 populations are quite different, when identical haplotypes are compared, their odds ratios are nearly the same. For all parental haplotypes, the transmission to diabetic offspring was similar for Korean and Caucasian families. The authors concluded that, not only by case-control comparison but also by transmission analyses of the haplotypes, that the susceptibility effects of DRB1-DQB1 haplotypes are consistent in Koreans and Caucasians. Thus, the influence of class II susceptibility and resistance alleles appears to transcend ethnic and geographic diversity of IDDM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11134105" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#94" class="mim-tip-reference" title="Onodera, T., Yoon, J.-W., Brown, K. S., Notkins, A. L. <strong>Evidence for a single locus controlling susceptibility to virus-induced diabetes mellitus.</strong> Nature 274: 693-696, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/209341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">209341</a>] [<a href="https://doi.org/10.1038/274693a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="209341">Onodera et al. (1978)</a> presented evidence that a single locus controls susceptibility to virus-induced diabetes mellitus in mice. They speculated that the gene might modulate expression of viral receptors on the beta cells of islets. DRw3 and DRw4 appear to be associated with JOD. The disease may be somewhat different depending on which is associated. The disease is more severe in homozygotes or genetic compounds (<a href="#12" class="mim-tip-reference" title="Bodmer, W. <strong>Personal Communication.</strong> Oxford, England 1978."None>Bodmer, 1978</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=209341" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#98" class="mim-tip-reference" title="Prochazka, M., Leiter, E. H., Serreze, D. V., Coleman, D. L. <strong>Three recessive loci required for insulin-dependent diabetes in nonobese diabetic mice.</strong> Science 237: 286-289, 1987. Note: Erratum: Science 242: 945 only, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2885918/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2885918</a>] [<a href="https://doi.org/10.1126/science.2885918" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2885918">Prochazka et al. (1987)</a> established a polygenic basis for susceptibility to IDDM in nonobese diabetic mice (NOD) by outcross to a related inbred strain, nonobese normal. Analysis of first and second backcross progeny showed that at least 3 recessive genes are required for development of overt diabetes. One of them was tightly linked to the major histocompatibility complex on chromosome 17 of the mouse; a second was localized proximal to the Thy-1/Alp-1 cluster on mouse chromosome 9. (In an erratum, the authors stated that the original recombinant designation was erroneous.) It may be that corresponding recessive genes are located on chromosomes 6 and 11 in man; the THY1 (<a href="/entry/188230">188230</a>) and APOA1 (<a href="/entry/107680">107680</a>) genes are on human 11q. By use of an affected sib pair method, however, <a href="#58" class="mim-tip-reference" title="Hyer, R. N., Julier, C., Buckley, J. D., Trucco, M., Rotter, J., Spielman, R., Barnett, A., Bain, S., Boitard, C., Deschamps, I., Todd, J. A., Bell, J. I., Lathrop, G. M. <strong>High-resolution linkage mapping for susceptibility genes in human polygenic disease: insulin-dependent diabetes mellitus and chromosome 11q.</strong> Am. J. Hum. Genet. 48: 243-257, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1990836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1990836</a>]" pmid="1990836">Hyer et al. (1991)</a> appeared to have excluded the possibility of an IDDM susceptibility gene on 11q (see <a href="/entry/125852">125852</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1990836+2885918" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Several features of the genetics and immunopathology of diabetes in the NOD mouse are closely similar to those of the human disease. Three murine diabetes susceptibility genes, Idd-1, Idd-3, and Idd-4, had been mapped, but only in the case of Idd-1 was there evidence concerning the identity of the gene product. Allelic variation within the murine immune response I-A(beta) gene and its human homolog, HLA-DQB1, correlated with susceptibility. <a href="#25" class="mim-tip-reference" title="Cornall, R. J., Prins, J.-B., Todd, J. A., Pressey, A., DeLarato, N. H., Wicker, L. S., Peterson, L. B. <strong>Type 1 diabetes in mice is linked to the interleukin-1 receptor and Lsh/Ity/Bcg genes on chromosome 1.</strong> Nature 353: 262-265, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1832743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1832743</a>] [<a href="https://doi.org/10.1038/353262a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1832743">Cornall et al. (1991)</a> mapped Idd-5 to the proximal region of mouse chromosome 1. This region contains at least 2 candidate susceptibility genes: the interleukin-1 receptor gene (see <a href="/entry/147810">147810</a>) and the Lsh/Ity/Bcg gene which encodes resistance to bacterial and parasitic infections and affects the function of macrophages (see <a href="/entry/209950">209950</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1832743" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#48" class="mim-tip-reference" title="Garchon, H.-J., Bedossa, P., Eloy, L., Bach, J.-F. <strong>Identification and mapping to chromosome 1 of a susceptibility locus for periinsulitis in non-obese diabetic mice.</strong> Nature 353: 260-262, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1896073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1896073</a>] [<a href="https://doi.org/10.1038/353260a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1896073">Garchon et al. (1991)</a> demonstrated close association of periinsulitis in the NOD mouse with a locus on chromosome 1. In the NOD mouse, furthermore, insulitis and early-onset diabetes had been linked to chromosomes 3 and 11, respectively (<a href="#135" class="mim-tip-reference" title="Todd, J. A., Aitman, T. J., Cornall, R. J., Ghosh, S., Hall, J. R. S., Hearne, C. M., Knight, A. M., Love, J. M., McAleer, M. A., Prins, J.-B., Rodrigues, N., Lathrop, M., Pressey, A., DeLarato, N. H., Peterson, L. B., Wicker, L. S. <strong>Genetic analysis of autoimmune type 1 diabetes mellitus in mice.</strong> Nature 351: 542-547, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1675432/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1675432</a>] [<a href="https://doi.org/10.1038/351542a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1675432">Todd et al., 1991</a>). <a href="#48" class="mim-tip-reference" title="Garchon, H.-J., Bedossa, P., Eloy, L., Bach, J.-F. <strong>Identification and mapping to chromosome 1 of a susceptibility locus for periinsulitis in non-obese diabetic mice.</strong> Nature 353: 260-262, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1896073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1896073</a>] [<a href="https://doi.org/10.1038/353260a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1896073">Garchon et al. (1991)</a> suggested that the existence of conserved syntenies between the human and murine genomes point to possible IDDM genes on human chromosomes 1, 2, or 18. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1675432+1896073" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Overt type 1 diabetes is often preceded by the appearance of insulin autoantibodies. Furthermore, prophylactic administration of insulin to diabetes-prone rats, NOD mice, and human subjects results in protection from diabetes. These 2 observations suggest that an immune response to insulin is involved in the process of beta cell destruction in the pancreas. <a href="#33" class="mim-tip-reference" title="Daniel, D., Wegmann, D. R. <strong>Protection of nonobese diabetic mice from diabetes by intranasal or subcutaneous administration of insulin peptide B-(9-23).</strong> Proc. Nat. Acad. Sci. 93: 956-960, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8570667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8570667</a>] [<a href="https://doi.org/10.1073/pnas.93.2.956" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8570667">Daniel and Wegmann (1996)</a> noted that islet-infiltrating cells isolated from NOD mice are enriched for insulin-specific T cells, insulin-specific T cell clones are capable of adoptive transfer of diabetes, and epitopes present on residues 9-23 of the B chain appear to be dominant in this spontaneous response. Against this background, <a href="#33" class="mim-tip-reference" title="Daniel, D., Wegmann, D. R. <strong>Protection of nonobese diabetic mice from diabetes by intranasal or subcutaneous administration of insulin peptide B-(9-23).</strong> Proc. Nat. Acad. Sci. 93: 956-960, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8570667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8570667</a>] [<a href="https://doi.org/10.1073/pnas.93.2.956" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8570667">Daniel and Wegmann (1996)</a> tested the effect of either subcutaneous or intranasal administration of B-(9-23) on the incidence of diabetes in NOD mice. The results indicated to them that both modes of administration resulted in a marked delay in the onset and a decrease in the incidence of diabetes relative to mice given the control peptide, a tetanus toxin. The protective effect was associated with reduced T-cell proliferative response to B-(9-23) in B-(9-23)-treated mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8570667" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Amrani, A., Verdaguer, J., Serra, P., Tafuro, S., Tan, R., Santamaria, P. <strong>Progression of autoimmune diabetes driven by avidity maturation of a T-cell population.</strong> Nature 406: 739-742, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10963600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10963600</a>] [<a href="https://doi.org/10.1038/35021081" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10963600">Amrani et al. (2000)</a> demonstrated that progression of pancreatic islet inflammation to overt diabetes in NOD mice is driven by the 'avidity maturation' of a prevailing, pancreatic beta-cell-specific T lymphocyte population carrying the CD8 antigen (<a href="/entry/186910">186910</a>). This T lymphocyte population recognizes 2 related peptides, NRP and NRP-A7, in the context of H-2K(d) class I molecules of the major histocompatibility complex. As prediabetic NOD mice age, their islet-associated CD8+ T lymphocytes contain increasing numbers of NRP-A7-reactive cells, and these cells bind NRP-A7/H-2K(d) tetramers with increased specificity, increased avidity, and longer half-lives. Repeated treatment of prediabetic NOD mice with soluble NRP-A7 peptide blunts the avidity maturation of the NRP-A7-reactive-CD8+ T cell population. This inhibits the local production of T cells that are cytotoxic to beta cells, and halts the progression from severe insulitis to diabetes. <a href="#2" class="mim-tip-reference" title="Amrani, A., Verdaguer, J., Serra, P., Tafuro, S., Tan, R., Santamaria, P. <strong>Progression of autoimmune diabetes driven by avidity maturation of a T-cell population.</strong> Nature 406: 739-742, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10963600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10963600</a>] [<a href="https://doi.org/10.1038/35021081" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10963600">Amrani et al. (2000)</a> concluded that avidity maturation of pathogenic T-cell populations may be the key event in the progression of benign inflammation to overt disease in autoimmunity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10963600" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Given the presence of islet beta-cell-reactive autoantibodies in prediabetic nonobese diabetic mice, <a href="#49" class="mim-tip-reference" title="Greeley, S. A. W., Katsumata, M., Yu, L., Eisenbarth, G. S., Moore, D. J., Goodarzi, H., Barker, C. F., Naji, A., Noorchashm, H. <strong>Elimination of maternally transmitted autoantibodies prevents diabetes in nonobese diabetic mice.</strong> Nature Med. 8: 399-402, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11927947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11927947</a>] [<a href="https://doi.org/10.1038/nm0402-399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11927947">Greeley et al. (2002)</a> abrogated the maternal transmission of such antibodies in order to assess their influence on susceptibility of progeny to diabetes. First, they used B cell-deficient NOD mothers to eliminate the transmission of maternal immunoglobulins. In a complementary approach, they used immunoglobulin transgenic NOD mothers to exclude autoreactive specificities from the maternal B-cell repertoire. Finally, the authors implanted NOD embryos in pseudopregnant mothers of a nonautoimmune strain. In a commentary on the publication of <a href="#49" class="mim-tip-reference" title="Greeley, S. A. W., Katsumata, M., Yu, L., Eisenbarth, G. S., Moore, D. J., Goodarzi, H., Barker, C. F., Naji, A., Noorchashm, H. <strong>Elimination of maternally transmitted autoantibodies prevents diabetes in nonobese diabetic mice.</strong> Nature Med. 8: 399-402, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11927947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11927947</a>] [<a href="https://doi.org/10.1038/nm0402-399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11927947">Greeley et al. (2002)</a>, <a href="#143" class="mim-tip-reference" title="von Herrath, M., Bach, J.-F. <strong>Juvenile autoimmune diabetes: a pathogenic role for maternal antibodies?</strong> Nature Med. 8: 331-333, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11927933/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11927933</a>] [<a href="https://doi.org/10.1038/nm0402-331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11927933">von Herrath and Bach (2002)</a> noted that in the first experiment the incidence of diabetes was reduced to 25%, compared with 65% in offspring of B cell-competent mothers. The second experiment resulted in a more significant reduction: 20% of offspring developed diabetes versus 70% of offspring of nontransgenic mothers. In the third experiment, diabetes incidence was only 15% of offspring versus 73% of offspring of NOD mothers. <a href="#49" class="mim-tip-reference" title="Greeley, S. A. W., Katsumata, M., Yu, L., Eisenbarth, G. S., Moore, D. J., Goodarzi, H., Barker, C. F., Naji, A., Noorchashm, H. <strong>Elimination of maternally transmitted autoantibodies prevents diabetes in nonobese diabetic mice.</strong> Nature Med. 8: 399-402, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11927947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11927947</a>] [<a href="https://doi.org/10.1038/nm0402-399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11927947">Greeley et al. (2002)</a> concluded that the maternal transmission of antibodies is a critical environmental parameter influencing the ontogeny of T cell-mediated destruction of islet beta cells in NOD mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11927947+11927933" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#71" class="mim-tip-reference" title="Lang, K. S., Recher, M., Junt, T., Navarini, A. A., Harris, N. L., Freigang, S., Odermatt, B., Conrad, C., Ittner, L. M., Bauer, S., Luther, S. A., Uematsu, S., Akira, S., Hengartner, H., Zinkernagel, R. M. <strong>Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease.</strong> Nature Med. 11: 138-145, 2005. Note: Erratum: Nature Med. 11: 1256 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15654326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15654326</a>] [<a href="https://doi.org/10.1038/nm1176" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15654326">Lang et al. (2005)</a> investigated the circumstances under which CD8+ T cells specific for pancreatic beta islet antigens induce disease in mice expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) as a transgene under the control of the rat insulin promoter. In contrast to infection with LCMV, immunization with LCMV-GP-derived peptide did not induce autoimmune diabetes despite large numbers of autoreactive cytotoxic T cells; only subsequent treatment with Toll-like receptor (see <a href="/entry/601194">601194</a>) ligands elicited overt diabetes. This difference was critically regulated by the pancreas itself, which upregulated class I major histocompatibility complex (MHC) in response to systemic Toll-like receptor-triggered interferon-alpha (<a href="/entry/147660">147660</a>) production. <a href="#71" class="mim-tip-reference" title="Lang, K. S., Recher, M., Junt, T., Navarini, A. A., Harris, N. L., Freigang, S., Odermatt, B., Conrad, C., Ittner, L. M., Bauer, S., Luther, S. A., Uematsu, S., Akira, S., Hengartner, H., Zinkernagel, R. M. <strong>Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease.</strong> Nature Med. 11: 138-145, 2005. Note: Erratum: Nature Med. 11: 1256 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15654326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15654326</a>] [<a href="https://doi.org/10.1038/nm1176" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15654326">Lang et al. (2005)</a> concluded that the 'inflammatory status' of the target organ is a separate and limiting factor determining the development of autoimmune disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15654326" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The NOD mouse is not only the best model for spontaneous type 1 diabetes, but also for Sjogren syndrome (<a href="/entry/270150">270150</a>). In NOD mice, in which loss of salivary secretory function develops spontaneously (as in human Sjogren syndrome), <a href="#151" class="mim-tip-reference" title="Winer, S., Astsaturov, I., Cheung, R., Tsui, H., Song, A., Gaedigk, R., Winer, D., Sampson, A., McKerlie, C., Bookman, A., Dosch, H.-M. <strong>Primary Sjogren's syndrome and deficiency of ICA69.</strong> Lancet 360: 1063-1069, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12383988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12383988</a>] [<a href="https://doi.org/10.1016/S0140-6736(02)11144-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12383988">Winer et al. (2002)</a> found that disruption of the Ica69 gene (<a href="/entry/147625">147625</a>), which is expressed in salivary and lacrimal glands, prevented lacrimal gland disease and greatly reduced salivary gland disease. These animals developed type 1 diabetes with slight delay but at much the same incidence as wildtype animals, assigning a facultative rather than obligate role to ICA69 in the development of diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12383988" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#84" class="mim-tip-reference" title="Nakayama, M., Abiru, N., Moriyama, H., Babaya, N., Liu, E., Miao, D., Yu, L., Wegmann, D. R., Hutton, J. C., Elliott, J. F., Eisenbarth, G. S. <strong>Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice.</strong> Nature 435: 220-223, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15889095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15889095</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15889095[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature03523" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15889095">Nakayama et al. (2005)</a> showed that the proinsulin/insulin molecules have a sequence that is a primary target of the autoimmunity that causes diabetes of the NOD mouse. They created insulin-1 and insulin-2 gene knockouts combined with a mutated proinsulin transgene, in which residue 16 on the B chain was changed to alanine, in NOD mice. This mutation abrogated the T-cell stimulation of a series of the major insulin autoreactive NOD T-cell clones. Female mice with only the altered insulin did not develop insulin autoantibodies, insulitis, or autoimmune diabetes, in contrast with mice containing at least 1 copy of the native insulin gene. <a href="#84" class="mim-tip-reference" title="Nakayama, M., Abiru, N., Moriyama, H., Babaya, N., Liu, E., Miao, D., Yu, L., Wegmann, D. R., Hutton, J. C., Elliott, J. F., Eisenbarth, G. S. <strong>Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice.</strong> Nature 435: 220-223, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15889095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15889095</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15889095[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature03523" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15889095">Nakayama et al. (2005)</a> suggested that proinsulin is a primary autoantigen of the NOD mouse and speculated that organ-restricted autoimmune disorders with marked major histocompatibility complex restriction of disease are likely to have specific primary autoantigens. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15889095" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Treatment of NOD mice with end-stage disease by injection of donor splenocytes and complete Freund adjuvant eliminates autoimmunity and permanently restores normoglycemia. The return of endogenous insulin secretion is accompanied by the reappearance of pancreatic beta cells. <a href="#67" class="mim-tip-reference" title="Kodama, S., Kuhtreiber, W., Fujimura, S., Dale, E. A., Faustman, D. L. <strong>Islet regeneration during the reversal of autoimmune diabetes in NOD mice.</strong> Science 302: 1223-1227, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14615542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14615542</a>] [<a href="https://doi.org/10.1126/science.1088949" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14615542">Kodama et al. (2003)</a> showed that live donor male or labeled splenocytes administered to diabetic NOD females contain cells that rapidly differentiate into islet or ductal epithelial cells within the pancreas. Treatment with irradiated splenocytes is also followed by islet regeneration, but at a slower rate. The islets generated in both instances are persistent, functional, and apparent in all NOD hosts with permanent disease reversal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14615542" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Chong, A. S., Shen, J., Tao, J., Yin, D., Kuznetsov, A., Hara, M., Philipson, L. H. <strong>Reversal of diabetes in non-obese diabetic mice without spleen cell-derived beta cell regeneration.</strong> Science 311: 1774-1775, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16556844/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16556844</a>] [<a href="https://doi.org/10.1126/science.1123510" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16556844">Chong et al. (2006)</a>, <a href="#92" class="mim-tip-reference" title="Nishio, J., Gaglia, J. L., Turvey, S. E., Campbell, C., Benoist, C., Mathis, D. <strong>Islet recovery and reversal of murine type 1 diabetes in the absence of any infused spleen cell contribution.</strong> Science 311: 1775-1778, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16556845/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16556845</a>] [<a href="https://doi.org/10.1126/science.1124004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16556845">Nishio et al. (2006)</a>, and <a href="#127" class="mim-tip-reference" title="Suri, A., Calderon, B., Esparza, T. J., Frederick, K., Bittner, P., Unanue, E. R. <strong>Immunological reversal of autoimmune diabetes without hematopoietic replacement of beta cells.</strong> Science 311: 1778-1780, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16556846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16556846</a>] [<a href="https://doi.org/10.1126/science.1123500" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16556846">Suri et al. (2006)</a> replicated the studies of <a href="#67" class="mim-tip-reference" title="Kodama, S., Kuhtreiber, W., Fujimura, S., Dale, E. A., Faustman, D. L. <strong>Islet regeneration during the reversal of autoimmune diabetes in NOD mice.</strong> Science 302: 1223-1227, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14615542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14615542</a>] [<a href="https://doi.org/10.1126/science.1088949" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14615542">Kodama et al. (2003)</a>. <a href="#17" class="mim-tip-reference" title="Chong, A. S., Shen, J., Tao, J., Yin, D., Kuznetsov, A., Hara, M., Philipson, L. H. <strong>Reversal of diabetes in non-obese diabetic mice without spleen cell-derived beta cell regeneration.</strong> Science 311: 1774-1775, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16556844/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16556844</a>] [<a href="https://doi.org/10.1126/science.1123510" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16556844">Chong et al. (2006)</a> cured 32% of NOD mice of established diabetes (greater than 340 milligrams per deciliter blood glucose), although beta cells in these mice were not derived from donor splenocytes. <a href="#92" class="mim-tip-reference" title="Nishio, J., Gaglia, J. L., Turvey, S. E., Campbell, C., Benoist, C., Mathis, D. <strong>Islet recovery and reversal of murine type 1 diabetes in the absence of any infused spleen cell contribution.</strong> Science 311: 1775-1778, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16556845/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16556845</a>] [<a href="https://doi.org/10.1126/science.1124004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16556845">Nishio et al. (2006)</a> provided data indicating that the recovered islets were all of host origin, reflecting that the diabetic NOD mice actually retained substantial beta cell mass, which can be rejuvenated/regenerated to reverse disease upon adjuvant-dependent dampening of autoimmunity. Their study reported a 70% reversion rate to spontaneous diabetes among the treated animals compared to an 8% reversion rate in the study by <a href="#67" class="mim-tip-reference" title="Kodama, S., Kuhtreiber, W., Fujimura, S., Dale, E. A., Faustman, D. L. <strong>Islet regeneration during the reversal of autoimmune diabetes in NOD mice.</strong> Science 302: 1223-1227, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14615542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14615542</a>] [<a href="https://doi.org/10.1126/science.1088949" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14615542">Kodama et al. (2003)</a>. <a href="#127" class="mim-tip-reference" title="Suri, A., Calderon, B., Esparza, T. J., Frederick, K., Bittner, P., Unanue, E. R. <strong>Immunological reversal of autoimmune diabetes without hematopoietic replacement of beta cells.</strong> Science 311: 1778-1780, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16556846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16556846</a>] [<a href="https://doi.org/10.1126/science.1123500" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16556846">Suri et al. (2006)</a> found that islet transplantation and immunization with Freund complete adjuvant along with multiple injections of allogeneic male splenocytes allowed for survival of transplanted islets and recovery of endogenous beta-cell function in a proportion of mice, but with no evidence for allogeneic splenocyte-derived differentiation of new islet beta cells. <a href="#127" class="mim-tip-reference" title="Suri, A., Calderon, B., Esparza, T. J., Frederick, K., Bittner, P., Unanue, E. R. <strong>Immunological reversal of autoimmune diabetes without hematopoietic replacement of beta cells.</strong> Science 311: 1778-1780, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16556846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16556846</a>] [<a href="https://doi.org/10.1126/science.1123500" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16556846">Suri et al. (2006)</a> concluded that control of autoimmune disease at a crucial time in diabetogenesis can result in recovery of beta-cell function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14615542+16556844+16556845+16556846" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a commentary on the papers of <a href="#16" class="mim-tip-reference" title="Chong, A. S., Shen, J., Tao, J., Yin, D., Kuznetsov, A., Hara, M., Philipson, L. H. <strong>Response to comment on Chong et al. on diabetes reversal in NOD mice.</strong> Science 314: 1243 only, 2006."None>Chong et al. (2006)</a>, <a href="#93" class="mim-tip-reference" title="Nishio, J., Gaglia, J. L., Turvey, S. E., Campbell, C., Benoist, C., Mathis, D. <strong>Response to comment on Nishio et al. on diabetes reversal in NOD mice.</strong> Science 314: 1243 only, 2006."None>Nishio et al. (2006)</a>, and <a href="#128" class="mim-tip-reference" title="Suri, A., Unanue, E. R. <strong>Response to comment on Suri et al. on diabetes reversal in NOD mice.</strong> Science 314: 1243 only, 2006."None>Suri and Unanue (2006)</a>, <a href="#41" class="mim-tip-reference" title="Faustman, D. L., Tran, S. D., Kodama, S., Lodde, B. M., Szalayova, I., Key, S., Toth, Z., Mezey, E. <strong>Comment on papers by Chong et al., Nishio et al., and Suri et al. on diabetes reversal in NOD mice.</strong> Science 314: 1243 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17124308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17124308</a>] [<a href="https://doi.org/10.1126/science.1129918" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17124308">Faustman et al. (2006)</a> stated that while these groups did not find that donor spleen cells contribute to the regeneration of the pancreas, <a href="#41" class="mim-tip-reference" title="Faustman, D. L., Tran, S. D., Kodama, S., Lodde, B. M., Szalayova, I., Key, S., Toth, Z., Mezey, E. <strong>Comment on papers by Chong et al., Nishio et al., and Suri et al. on diabetes reversal in NOD mice.</strong> Science 314: 1243 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17124308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17124308</a>] [<a href="https://doi.org/10.1126/science.1129918" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17124308">Faustman et al. (2006)</a> confirmed the results of <a href="#67" class="mim-tip-reference" title="Kodama, S., Kuhtreiber, W., Fujimura, S., Dale, E. A., Faustman, D. L. <strong>Islet regeneration during the reversal of autoimmune diabetes in NOD mice.</strong> Science 302: 1223-1227, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14615542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14615542</a>] [<a href="https://doi.org/10.1126/science.1088949" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14615542">Kodama et al. (2003)</a> of a direct splenocyte contribution to insulin-expressing cells of the islets. In response to the comments by <a href="#41" class="mim-tip-reference" title="Faustman, D. L., Tran, S. D., Kodama, S., Lodde, B. M., Szalayova, I., Key, S., Toth, Z., Mezey, E. <strong>Comment on papers by Chong et al., Nishio et al., and Suri et al. on diabetes reversal in NOD mice.</strong> Science 314: 1243 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17124308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17124308</a>] [<a href="https://doi.org/10.1126/science.1129918" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17124308">Faustman et al. (2006)</a>, <a href="#16" class="mim-tip-reference" title="Chong, A. S., Shen, J., Tao, J., Yin, D., Kuznetsov, A., Hara, M., Philipson, L. H. <strong>Response to comment on Chong et al. on diabetes reversal in NOD mice.</strong> Science 314: 1243 only, 2006."None>Chong et al. (2006)</a>, <a href="#93" class="mim-tip-reference" title="Nishio, J., Gaglia, J. L., Turvey, S. E., Campbell, C., Benoist, C., Mathis, D. <strong>Response to comment on Nishio et al. on diabetes reversal in NOD mice.</strong> Science 314: 1243 only, 2006."None>Nishio et al. (2006)</a>, <a href="#128" class="mim-tip-reference" title="Suri, A., Unanue, E. R. <strong>Response to comment on Suri et al. on diabetes reversal in NOD mice.</strong> Science 314: 1243 only, 2006."None>Suri and Unanue (2006)</a> stated that they could not detect spleen cell transdifferentiation of spleen cells into beta cells in NOD mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14615542+17124308" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#42" class="mim-tip-reference" title="Faustman, D. L. <strong>Permanent reversal of diabetes in NOD mice. (Letter)</strong> Science 317: 196 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17626866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17626866</a>] [<a href="https://doi.org/10.1126/science.317.5835.196a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17626866">Faustman (2007)</a> refuted comments made by <a href="#92" class="mim-tip-reference" title="Nishio, J., Gaglia, J. L., Turvey, S. E., Campbell, C., Benoist, C., Mathis, D. <strong>Islet recovery and reversal of murine type 1 diabetes in the absence of any infused spleen cell contribution.</strong> Science 311: 1775-1778, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16556845/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16556845</a>] [<a href="https://doi.org/10.1126/science.1124004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16556845">Nishio et al. (2006)</a> that they did not use the appropriate controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16556845+17626866" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#149" class="mim-tip-reference" title="Wen, L., Ley, R. E., Volchkov, P. Y., Stranges, P. B., Avanesyan, L., Stonebraker, A. C., Hu, C., Wong, F. S., Szot, G. L., Bluestone, J. A., Gordon, J. I., Chervonsky, A. V. <strong>Innate immunity and intestinal microbiota in the development of type 1 diabetes.</strong> Nature 455: 1109-1113, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18806780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18806780</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18806780[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18806780">Wen et al. (2008)</a> showed that specific pathogen-free NOD mice lacking Myd88 (<a href="/entry/602170">602170</a>), an adaptor for multiple innate immune receptors that recognize microbial stimuli, do not develop type 1 diabetes. The effect is dependent on commensal microbes because germ-free Myd88-negative NOD mice develop robust diabetes, whereas colonization of these germ-free Myd88-negative NOD mice with a defined microbial consortium (representing bacterial phyla normally present in human gut) attenuates type 1 diabetes. <a href="#149" class="mim-tip-reference" title="Wen, L., Ley, R. E., Volchkov, P. Y., Stranges, P. B., Avanesyan, L., Stonebraker, A. C., Hu, C., Wong, F. S., Szot, G. L., Bluestone, J. A., Gordon, J. I., Chervonsky, A. V. <strong>Innate immunity and intestinal microbiota in the development of type 1 diabetes.</strong> Nature 455: 1109-1113, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18806780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18806780</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18806780[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18806780">Wen et al. (2008)</a> also found that Myd88 deficiency changes the composition of the distal gut microbiota, and that exposure to the microbiota of specific pathogen-free Myd88-negative NOD donors attenuates type 1 diabetes in germ-free NOD recipients. <a href="#149" class="mim-tip-reference" title="Wen, L., Ley, R. E., Volchkov, P. Y., Stranges, P. B., Avanesyan, L., Stonebraker, A. C., Hu, C., Wong, F. S., Szot, G. L., Bluestone, J. A., Gordon, J. I., Chervonsky, A. V. <strong>Innate immunity and intestinal microbiota in the development of type 1 diabetes.</strong> Nature 455: 1109-1113, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18806780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18806780</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18806780[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18806780">Wen et al. (2008)</a> concluded that, taken together, their findings indicated that interaction of the intestinal microbes with the innate immune system is a critical epigenetic factor modifying type 1 diabetes predisposition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18806780" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Reviews</em></strong></p><p>
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<a href="#134" class="mim-tip-reference" title="Tisch, R., McDevitt, H. <strong>Insulin-dependent diabetes mellitus.</strong> Cell 85: 291-297, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8616883/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8616883</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81106-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8616883">Tisch and McDevitt (1996)</a> reviewed the molecular understanding of the pathogenesis of this autoimmune disease. Complete molecular understanding may permit the design of rational and effective means of prevention. Prevention could then replace insulin therapy, which is effective but associated with long-term renal, vascular, and retinal complications. They pointed to the concordance rate of only 50% in monozygotic twins, indicating as yet unidentified environmental factors. There is a north-south gradient in incidence of the disease, with the highest incidence in northern Europe (1% to 1.5% in Finland) and decreasing incidence in more southerly and tropical locations. Although this suggests the effect of infectious agents in the nonobese diabetic (NOD) mouse, germ-free NOD mice have the highest incidence (nearly 100%) that has been seen in any NOD colony. <a href="#134" class="mim-tip-reference" title="Tisch, R., McDevitt, H. <strong>Insulin-dependent diabetes mellitus.</strong> Cell 85: 291-297, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8616883/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8616883</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81106-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8616883">Tisch and McDevitt (1996)</a> reviewed the role of the major histocompatibility complex, the autoantigens targeted in IDDM, the T-cell response in IDDM, and experience to date with immunotherapy. Even if safe, effective, and long-lasting immunotherapies are developed, their application presents a formidable challenge. Only 15% of new cases of IDDM occur in families with a previous case. Overt diabetes develops only when beta cell destruction is nearly complete, and the patient is asymptomatic for months or years until that point is reached. Thus, immunotherapy must be preventive, which requires inexpensive and accurate genetic, autoantibody, and T cell screening techniques. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8616883" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>As indicated, linkage studies have shown that type 1 diabetes in NOD mice is a polygenic disease involving more than 15 chromosome susceptibility regions. Despite extensive investigation, the identification of individual susceptibility genes either within or outside the major histocompatibility complex region has proved problematic because of the limitations of linkage analysis. <a href="#52" class="mim-tip-reference" title="Hamilton-Williams, E. E., Serreze, D. V., Charlton, B., Johnson, E. A., Marron, M. P., Mullbacher, A., Slattery, R. M. <strong>Transgenic rescue implicates beta-2-microglobulin as a diabetes susceptibility gene in nonobese diabetic (NOD) mice.</strong> Proc. Nat. Acad. Sci. 98: 11533-11538, 2001. Note: Erratum: Proc. Nat. Acad. Sci. 98: 13472 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11572996/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11572996</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11572996[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.191383798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11572996">Hamilton-Williams et al. (2001)</a> provided evidence implicating a single diabetes susceptibility gene that lies outside the MHC region, namely, beta-2-microglobulin (B2M; <a href="/entry/109700">109700</a>). Using allelic reconstitution by transgenic rescue, they showed that NOD mice expressing the B2m*a allele developed diabetes, whereas NOD mice expressing a murine B2m*b or human allele of B2M were protected. The murine B2m*a allele differs from the B2m*b allele at only a single amino acid. Mechanistic studies indicated that the absence of the NOD B2m*a isoform on nonhematopoietic cells inhibited the development or activation of diabetogenic T cells. <a href="#52" class="mim-tip-reference" title="Hamilton-Williams, E. E., Serreze, D. V., Charlton, B., Johnson, E. A., Marron, M. P., Mullbacher, A., Slattery, R. M. <strong>Transgenic rescue implicates beta-2-microglobulin as a diabetes susceptibility gene in nonobese diabetic (NOD) mice.</strong> Proc. Nat. Acad. Sci. 98: 11533-11538, 2001. Note: Erratum: Proc. Nat. Acad. Sci. 98: 13472 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11572996/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11572996</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11572996[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.191383798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11572996">Hamilton-Williams et al. (2001)</a> stated that it was not yet possible to determine whether subtle variations in B2M may also contribute to autoimmune diabetes in humans because the extent of polymorphism in this gene had not been extensively investigated. However, they noted that the B2m*a allele implicated as a dominant diabetes susceptibility gene in NOD mice is not a biologically aberrant variant but rather a common physiologically normal allele, which may exert its pathogenic functions only in certain combinatorial contexts. This supports the hypothesis of combinatorial context of 'normal' alleles (<a href="#88" class="mim-tip-reference" title="Nerup, J., Mandrup-Poulsen, T., Helqvist, S., Andersen, H. U., Pociot, F., Reimers, J. I., Cuartero, B. G., Karlsen, A. E., Bjerre, U., Lorenzen, T. <strong>On the pathogenesis of IDDM.</strong> Diabetologia 37 (Suppl. 2): S82-S89, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7821744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7821744</a>] [<a href="https://doi.org/10.1007/BF00400830" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7821744">Nerup et al., 1994</a>). They also noted that further support for this concept is strong linkage disequilibrium implicating a number of other physiologically normal cytokine variants as candidate susceptibility genes for diabetes (<a href="#76" class="mim-tip-reference" title="Lyons, P. A., Armitage, N., Argentina, F., Denny, P., Hill, N. J., Lord, C. J., Wilusz, M. B., Peterson, L. B., Wicker, L. S., Todd, J. A. <strong>Congenic mapping of the type 1 diabetes locus, Idd3, to a 780-kb region of mouse chromosome 3: identification of a candidate segment of ancestral DNA by haplotype mapping.</strong> Genome Res. 10: 446-453, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10779485/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10779485</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10779485[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gr.10.4.446" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10779485">Lyons et al., 2000</a>; <a href="#80" class="mim-tip-reference" title="Morahan, G., Huang, D., Ymer, S. I., Cancilla, M. R., Stephen, K., Dabadghao, P., Werther, G., Tait, B. D., Harrison, L. C., Colman, P. G. <strong>Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL12B allele.</strong> Nature Genet. 27: 218-221, 2001. Note: Erratum: Nature Genet. 27: 346 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175794</a>] [<a href="https://doi.org/10.1038/84872" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175794">Morahan et al., 2001</a>); see <a href="/entry/605998">605998</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7821744+10779485+11572996+11175794" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#144" class="mim-tip-reference" title="Vyse, T. J., Todd, J. A. <strong>Genetic analysis of autoimmune disease.</strong> Cell 85: 311-318, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8616887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8616887</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81110-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8616887">Vyse and Todd (1996)</a> gave a general review of genetic analyses of autoimmune diseases, including this one. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8616887" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using synalbumin insulin antagonism as a test, <a href="#141" class="mim-tip-reference" title="Vallance-Owen, J. <strong>The inheritance of essential diabetes mellitus from studies of synalbumin insulin antagonist.</strong> Diabetologia 2: 248-252, 1966.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6005204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6005204</a>] [<a href="https://doi.org/10.1007/BF01268181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6005204">Vallance-Owen (1966)</a> studied 9 families containing 16 overt cases of diabetes mellitus and concluded that the state of synalbumin positivity is a dominant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6005204" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Adams1984" class="mim-tip-reference" title="Adams, D. D., Adams, Y. J., Knight, J. G., McCall, J., White, P., Horrocks, R., van Loghem, E. <strong>A solution to the genetic and environmental puzzles of insulin-dependent diabetes mellitus.</strong> Lancet 323: 420-424, 1984. Note: Originally Volume I.">Adams et al. (1984)</a>; <a href="#Barbosa1982" class="mim-tip-reference" title="Barbosa, J., Rich, S., Dunsworth, T., Swanson, J. <strong>Linkage disequilibrium between insulin-dependent diabetes and the Kidd blood group Jk(b) allele.</strong> J. Clin. Endocr. Metab. 55: 193-195, 1982.">Barbosa et al. (1982)</a>; <a href="#Creutzfeldt1976" class="mim-tip-reference" title="Creutzfeldt, W., Kobberling, J., Neel, J. V. <strong>The Genetics of Diabetes Mellitus.</strong> Berlin and New York: Springer (pub.) 1976.">Creutzfeldt et al.
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(1976)</a>; <a href="#Neel1965" class="mim-tip-reference" title="Neel, J. V., Fajans, S. S., Conn, J. W., Davidson, R. T. <strong>Diabetes mellitus. In: Neel, J. V.; Shaw, M. W.; Schull, W. J. (eds.): Genetics and Epidemiology of Chronic Diseases.</strong> Washington, D. C.: Government Printing Office (pub.) 1965.">Neel et al. (1965)</a>; <a href="#Neel1977" class="mim-tip-reference" title="Neel, J. V. <strong>The genetics of juvenile-onset-type diabetes mellitus.</strong> New Eng. J. Med. 297: 1062-1063, 1977.">Neel (1977)</a>; <a href="#Pyke1970" class="mim-tip-reference" title="Pyke, D. A. <strong>The genetics of diabetes.</strong> Postgrad. Med. J. 46: 604-606, 1970.">Pyke (1970)</a>; <a href="#Renold1972" class="mim-tip-reference" title="Renold, A. E., Stauffacher, W., Cahill, G. F., Jr. <strong>Diabetes mellitus. In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S. (eds.): The Metabolic Basis of Inherited Disease. (3rd ed.)</strong> New York: McGraw-Hill (pub.) 1972. Pp. 83-118.">Renold et al.
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(1972)</a>; <a href="#Risch1984" class="mim-tip-reference" title="Risch, N. <strong>Segregation analysis incorporating linkage markers. I. Single-locus models with an application to type I diabetes.</strong> Am. J. Hum. Genet. 36: 363-386, 1984.">Risch (1984)</a>; <a href="#Rosenthal1976" class="mim-tip-reference" title="Rosenthal, M. B., Goldfine, I. D., Siperstein, M. D. <strong>Genetic origin of diabetes. (Letter)</strong> Lancet 308: 908-909, 1976. Note: Originally Volume II.">Rosenthal et al. (1976)</a>; <a href="#Simpson1964" class="mim-tip-reference" title="Simpson, N. E. <strong>Multifactorial inheritance: a possible hypothesis for diabetes.</strong> Diabetes 13: 462-471, 1964.">Simpson (1964)</a>; <a href="#Steinberg1970" class="mim-tip-reference" title="Steinberg, A. G., Rushforth, N. B., Bennett, P. H., Burch, T. A., Miller, M. <strong>On the genetics of diabetes mellitus. In: Cerasi, E.; Luft, R. (eds.): Proc. Nobel Symposium XIII: On the Pathogenesis of Diabetes Mellitus.</strong> New York: Wiley (pub.) 1970. P. 237.">Steinberg et al. (1970)</a>; <a href="#Suarez1978" class="mim-tip-reference" title="Suarez, B. K., Hodge, S. E., Rice, J., Reich, T. <strong>Absence of tight linkage between HLA and the locus for juvenile diabetes. (Abstract)</strong> Am. J. Hum. Genet. 30: 68A, 1978.">Suarez et al. (1978)</a>; <a href="#Vinik1974" class="mim-tip-reference" title="Vinik, A. I., Kalk, W. J., Jackson, W. P. U. <strong>A unifying hypothesis for hereditary and acquired diabetes.</strong> Lancet 303: 485-486, 1974. Note: Originally Volume I.">Vinik et al. (1974)</a>; <a href="#Zonana1976" class="mim-tip-reference" title="Zonana, J., Rimoin, D. L. <strong>Inheritance of diabetes mellitus.</strong> New Eng. J. Med. 295: 603-605, 1976.">Zonana and Rimoin (1976)</a>
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Adams, D. D., Adams, Y. J., Knight, J. G., McCall, J., White, P., Horrocks, R., van Loghem, E.
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<strong>A solution to the genetic and environmental puzzles of insulin-dependent diabetes mellitus.</strong>
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Lancet 323: 420-424, 1984. Note: Originally Volume I.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6142151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6142151</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6142151" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Amrani, A., Verdaguer, J., Serra, P., Tafuro, S., Tan, R., Santamaria, P.
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<strong>Progression of autoimmune diabetes driven by avidity maturation of a T-cell population.</strong>
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Nature 406: 739-742, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10963600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10963600</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10963600" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Baisch, J. M., Weeks, T., Giles, R., Hoover, M., Stastny, P., Capra, J. D.
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<strong>Analysis of HLA-DQ genotypes and susceptibility in insulin-dependent diabetes mellitus.</strong>
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New Eng. J. Med. 322: 1836-1841, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2348836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2348836</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2348836" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Bao, M.-Z., Wang, J.-X., Dorman, J. S., Trucco, M.
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<strong>HLA-DQ-beta non-asp-57 allele and incidence of diabetes in China and the USA. (Letter)</strong>
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Lancet 334: 497-498, 1989. Note: Originally Volume II.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2570199/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2570199</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2570199" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Barbosa, J., Chern, M. M., Noreen, H., Anderson, V. E., Yunis, E. J.
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<strong>Analysis of linkage between the major histocompatibility system and juvenile, insulin-dependent diabetes in multiplex families: reanalysis of data.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/670405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">670405</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=670405" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>Linkage disequilibrium between insulin-dependent diabetes and the Kidd blood group Jk(b) allele.</strong>
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J. Clin. Endocr. Metab. 55: 193-195, 1982.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6951830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6951830</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6951830" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Barrett, J. C., Clayton, D. G., Concannon, P., Akolkar, B., Cooper, J. D., Erlich, H. A., Julier, C., Morahan, G., Nerup, J., Nierras, C., Plagnol, V., Pociot, F., Schuilenburg, H., Smyth, D. J., Stevens, H., Todd, J. A., Walker, N. M., Rich, S. S., Type 1 Diabetes Genetics Consortium.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19430480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19430480</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19430480" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.381" target="_blank">Full Text</a>]
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Bell, G. I., Horita, S., Karam, J. H.
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<strong>A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus.</strong>
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Diabetes 33: 176-183, 1984.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6363172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6363172</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6363172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.2337/diab.33.2.176" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM197812282992605" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/10.19.2025" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.2337/diab.24.4.345" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.93.2.956" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/324341" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1129918" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.317.5835.196a" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18806780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18806780</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18806780[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18806780" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature07336" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="150" class="mim-anchor"></a>
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<a id="Wenzlau2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wenzlau, J. M., Juhl, K., Yu, L., Moua, O., Sarkar, S. A., Gottlieb, P., Rewers, M., Eisenbarth, G. S., Jensen, J., Davidson, H. W., Hutton, J. C.
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<strong>The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes.</strong>
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Proc. Nat. Acad. Sci. 104: 17040-17045, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17942684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17942684</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17942684[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17942684" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0705894104" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="151" class="mim-anchor"></a>
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<a id="Winer2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Winer, S., Astsaturov, I., Cheung, R., Tsui, H., Song, A., Gaedigk, R., Winer, D., Sampson, A., McKerlie, C., Bookman, A., Dosch, H.-M.
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|
<strong>Primary Sjogren's syndrome and deficiency of ICA69.</strong>
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|
Lancet 360: 1063-1069, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12383988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12383988</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12383988" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/S0140-6736(02)11144-5" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="152" class="mim-anchor"></a>
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<a id="Woodrow1975" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Woodrow, J. C., Cudworth, A. G.
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<strong>HL-A8 and W15 in diabetes mellitus. (Letter)</strong>
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Lancet 305: 803 only, 1975. Note: Originally Volume I.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/48026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">48026</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=48026" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(75)92467-8" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="153" class="mim-anchor"></a>
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<a id="Zalloua2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zalloua, P. A., Azar, S. T., Delepine, M., Makhoul, N. J., Blanc, H., Sanyoura, M., Lavergne, A., Stankov, K., Lemainque, A., Baz, P., Julier, C.
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<strong>WFS1 mutations are frequent monogenic causes of juvenile-onset diabetes mellitus in Lebanon.</strong>
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Hum. Molec. Genet. 17: 4012-4021, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18806274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18806274</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18806274" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddn304" target="_blank">Full Text</a>]
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<li>
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<a id="154" class="mim-anchor"></a>
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<a id="Zonana1976" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zonana, J., Rimoin, D. L.
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<strong>Inheritance of diabetes mellitus.</strong>
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New Eng. J. Med. 295: 603-605, 1976.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/986004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">986004</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=986004" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJM197609092951106" target="_blank">Full Text</a>]
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<a id="contributors" class="mim-anchor"></a>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 03/03/2020
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 10/07/2019<br>George E. Tiller - updated : 9/16/2013<br>Marla J. F. O'Neill - updated : 5/10/2012<br>Marla J. F. O'Neill - updated : 9/22/2011<br>Ada Hamosh - updated : 4/28/2010<br>Marla J. F. O'Neill - updated : 4/19/2010<br>Marla J. F. O'Neill - updated : 1/29/2010<br>Marla J. F. O'Neill - updated : 10/12/2009<br>Ada Hamosh - updated : 9/8/2009<br>Marla J. F. O'Neill - updated : 4/28/2009<br>Ada Hamosh - updated : 4/16/2009<br>Marla J. F. O'Neill - updated : 2/11/2009<br>Ada Hamosh - updated : 11/26/2008<br>Marla J. F. O'Neill - updated : 3/20/2008<br>Marla J. F. O'Neill - updated : 11/9/2007<br>Ada Hamosh - updated : 8/13/2007<br>Ada Hamosh - updated : 7/31/2007<br>Ada Hamosh - updated : 7/19/2007<br>Marla J. F. O'Neill - updated : 2/26/2007<br>Ada Hamosh - updated : 1/25/2007<br>Victor A. McKusick - updated : 9/26/2006<br>Cassandra L. Kniffin - updated : 4/17/2006<br>Ada Hamosh - updated : 4/11/2006<br>Marla J. F. O'Neill - updated : 1/4/2006<br>Marla J. F. O'Neill - updated : 7/8/2005<br>Ada Hamosh - updated : 5/25/2005<br>Marla J. F. O'Neill - updated : 3/21/2005<br>George E. Tiller - updated : 2/23/2005<br>Victor A. McKusick - updated : 5/7/2004<br>John A. Phillips, III - updated : 2/9/2004<br>Ada Hamosh - updated : 12/3/2003<br>Victor A. McKusick - updated : 11/27/2002<br>Ada Hamosh - updated : 4/9/2002<br>John A. Phillips, III - updated : 3/14/2002<br>George E. Tiller - updated : 2/4/2002<br>Victor A. McKusick - updated : 12/20/2001<br>Victor A. McKusick - updated : 11/1/2001<br>Victor A. McKusick - updated : 10/23/2001<br>John A. Phillips, III - updated : 7/27/2001<br>John A. Phillips, III - updated : 7/11/2001<br>John A. Phillips, III - updated : 3/5/2001<br>Michael J. Wright - updated : 1/8/2001<br>Ada Hamosh - updated : 12/15/2000<br>Ada Hamosh - updated : 11/30/2000<br>Ada Hamosh - updated : 8/14/2000<br>John A. Phillips, III - updated : 8/10/2000<br>Victor A. McKusick - updated : 7/14/2000<br>George E. Tiller - updated : 6/30/2000<br>Ada Hamosh - updated : 4/20/2000<br>John A. Phillips, III - updated : 4/3/2000<br>Victor A. McKusick - updated : 2/7/2000<br>John A. Phillips, III - updated : 9/21/1999<br>Victor A. McKusick - updated : 2/27/1999<br>Victor A. McKusick - updated : 6/24/1998<br>Victor A. McKusick - updated : 3/25/1998
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</span>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/3/1986
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 01/25/2024
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</span>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 01/22/2024<br>carol : 09/04/2020<br>carol : 09/03/2020<br>carol : 04/08/2020<br>carol : 03/03/2020<br>carol : 10/08/2019<br>alopez : 10/07/2019<br>alopez : 08/12/2016<br>carol : 07/09/2016<br>carol : 4/8/2016<br>mgross : 10/4/2013<br>alopez : 9/16/2013<br>carol : 4/18/2013<br>terry : 4/1/2013<br>terry : 11/27/2012<br>terry : 8/31/2012<br>terry : 7/6/2012<br>carol : 5/10/2012<br>terry : 5/10/2012<br>carol : 9/23/2011<br>terry : 9/22/2011<br>wwang : 11/19/2010<br>terry : 11/12/2010<br>alopez : 11/11/2010<br>alopez : 11/10/2010<br>mgross : 9/3/2010<br>terry : 8/24/2010<br>alopez : 4/29/2010<br>terry : 4/28/2010<br>alopez : 4/22/2010<br>alopez : 4/22/2010<br>alopez : 4/21/2010<br>terry : 4/19/2010<br>carol : 2/4/2010<br>alopez : 1/29/2010<br>wwang : 10/29/2009<br>terry : 10/12/2009<br>alopez : 9/10/2009<br>alopez : 9/9/2009<br>terry : 9/8/2009<br>wwang : 7/29/2009<br>wwang : 5/6/2009<br>terry : 4/28/2009<br>alopez : 4/22/2009<br>terry : 4/16/2009<br>terry : 2/20/2009<br>carol : 2/13/2009<br>wwang : 2/12/2009<br>terry : 2/11/2009<br>carol : 1/7/2009<br>carol : 1/7/2009<br>alopez : 12/9/2008<br>terry : 11/26/2008<br>alopez : 8/28/2008<br>wwang : 3/25/2008<br>terry : 3/20/2008<br>wwang : 11/19/2007<br>terry : 11/9/2007<br>carol : 8/14/2007<br>terry : 8/13/2007<br>terry : 7/31/2007<br>alopez : 7/24/2007<br>terry : 7/19/2007<br>carol : 6/13/2007<br>wwang : 2/26/2007<br>alopez : 1/25/2007<br>terry : 1/25/2007<br>terry : 11/15/2006<br>alopez : 10/4/2006<br>terry : 9/26/2006<br>wwang : 4/24/2006<br>ckniffin : 4/17/2006<br>alopez : 4/11/2006<br>terry : 4/11/2006<br>alopez : 3/15/2006<br>wwang : 1/9/2006<br>terry : 1/4/2006<br>wwang : 7/20/2005<br>wwang : 7/15/2005<br>terry : 7/8/2005<br>wwang : 6/23/2005<br>wwang : 6/21/2005<br>tkritzer : 5/26/2005<br>terry : 5/25/2005<br>wwang : 3/23/2005<br>wwang : 3/21/2005<br>tkritzer : 3/7/2005<br>terry : 2/23/2005<br>alopez : 9/9/2004<br>carol : 5/25/2004<br>alopez : 5/17/2004<br>alopez : 5/17/2004<br>alopez : 5/17/2004<br>alopez : 5/17/2004<br>terry : 5/7/2004<br>carol : 3/17/2004<br>alopez : 2/9/2004<br>alopez : 12/8/2003<br>terry : 12/3/2003<br>tkritzer : 11/27/2002<br>alopez : 4/19/2002<br>cwells : 4/17/2002<br>cwells : 4/11/2002<br>terry : 4/9/2002<br>alopez : 3/14/2002<br>terry : 3/8/2002<br>cwells : 2/25/2002<br>cwells : 2/20/2002<br>cwells : 2/18/2002<br>cwells : 2/4/2002<br>alopez : 1/11/2002<br>cwells : 1/9/2002<br>terry : 12/20/2001<br>carol : 11/20/2001<br>mcapotos : 11/20/2001<br>mcapotos : 11/15/2001<br>terry : 11/1/2001<br>carol : 10/31/2001<br>mcapotos : 10/30/2001<br>terry : 10/23/2001<br>mgross : 7/27/2001<br>alopez : 7/11/2001<br>carol : 6/5/2001<br>alopez : 3/14/2001<br>alopez : 3/5/2001<br>mcapotos : 2/21/2001<br>alopez : 1/8/2001<br>mgross : 12/15/2000<br>terry : 12/15/2000<br>carol : 12/1/2000<br>terry : 11/30/2000<br>carol : 10/25/2000<br>alopez : 8/16/2000<br>terry : 8/14/2000<br>mgross : 8/10/2000<br>carol : 7/14/2000<br>terry : 7/14/2000<br>alopez : 6/30/2000<br>alopez : 4/20/2000<br>mgross : 4/19/2000<br>terry : 4/3/2000<br>mcapotos : 2/11/2000<br>terry : 2/7/2000<br>alopez : 12/3/1999<br>carol : 9/29/1999<br>mgross : 9/21/1999<br>jlewis : 6/25/1999<br>carol : 4/4/1999<br>carol : 2/27/1999<br>dkim : 12/9/1998<br>dkim : 7/24/1998<br>dholmes : 7/22/1998<br>alopez : 6/29/1998<br>terry : 6/24/1998<br>terry : 5/29/1998<br>alopez : 3/25/1998<br>terry : 3/19/1998<br>jenny : 7/2/1997<br>mark : 8/22/1996<br>terry : 8/21/1996<br>terry : 8/20/1996<br>terry : 8/19/1996<br>terry : 8/17/1996<br>mark : 8/15/1996<br>marlene : 8/6/1996<br>terry : 8/2/1996<br>mark : 2/9/1996<br>terry : 2/8/1996<br>mark : 12/13/1995<br>mark : 10/22/1995<br>terry : 6/24/1995<br>phil : 3/7/1995<br>carol : 1/23/1995<br>davew : 8/26/1994<br>mimadm : 4/26/1994
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</span>
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<h3>
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<span class="mim-font">
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<strong>%</strong> 222100
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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TYPE 1 DIABETES MELLITUS; T1D
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</span>
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</h3>
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</div>
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<div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</p>
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<div>
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<h4>
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<span class="mim-font">
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DIABETES MELLITUS, INSULIN-DEPENDENT; IDDM<br />
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JUVENILE-ONSET DIABETES; JOD
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</span>
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</h4>
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</div>
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<div>
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<br />
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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TYPE 1 DIABETES MELLITUS 1, INCLUDED; T1D1, INCLUDED
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</span>
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</div>
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<div>
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<span class="h4 mim-font">
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DIABETES MELLITUS, INSULIN-DEPENDENT, 1, INCLUDED; IDDM1, INCLUDED<br />
|
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INSULIN-DEPENDENT DIABETES MELLITUS 1, INCLUDED
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</span>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<strong>SNOMEDCT:</strong> 46635009;
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<strong>ICD10CM:</strong> E10;
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<strong>DO:</strong> 9744;
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Cytogenetic location: 6p21.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 6:30,500,001-36,600,000 </span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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6p21.3
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<span class="mim-font">
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{Diabetes mellitus, insulin-dependent-1}
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<span class="mim-font">
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222100
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Autosomal recessive
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<span class="mim-font">
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2
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</table>
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<span class="mim-font">
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>Type 1 diabetes mellitus (T1D), also designated insulin-dependent diabetes mellitus (IDDM), is a disorder of glucose homeostasis characterized by susceptibility to ketoacidosis in the absence of insulin therapy. It is a genetically heterogeneous autoimmune disease affecting about 0.3% of Caucasian populations (Todd, 1990). Genetic studies of T1D have focused on the identification of loci associated with increased susceptibility to this multifactorial phenotype. </p><p>The classic phenotype of diabetes mellitus is polydipsia, polyphagia, and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.</p>
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<strong>Clinical Features</strong>
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<p>The term diabetes mellitus is not precisely defined and the lack of a consensus on diagnostic criteria has made its genetic analysis difficult. Diabetes mellitus is classified clinically into 2 major forms of the primary illness, insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM; 125853), and secondary forms related to gestation or medical disorders.</p><p>Appearance of the IDDM phenotype is thought to require a predisposing genetic background and interaction with other environmental factors. Rotter and Rimoin (1978) hypothesized that there are at least 2 forms of IDDM: a B8 (DR3)-associated form characterized by pancreatic autoimmunity, and a B15-associated form characterized by antibody response to exogenous insulin. Interestingly, the DR3 and DR4 alleles seem to have a synergistic effect on the predisposition to IDDM based on the greatly increased risk observed in persons having both the B8 and B15 antigens (Svejgaard and Ryder, 1977). Rotter and Rimoin (1979) hypothesized a combined form. Tolins and Raij (1988) cited clinical and experimental evidence to support the idea that those IDDM patients in whom diabetic nephropathy (see 603933) eventually develops may have a genetic predisposition to essential hypertension. </p><p>Gambelunghe et al. (2001) noted heterogeneity of the clinical and immunologic features of IDDM in relation to age at clinical onset. Childhood IDDM is characterized by an abrupt onset and ketosis and is associated with HLA-DRB1*04-DQA1*0301-DQB1*0302 and a high frequency of insulin and IA-2 autoantibodies. On the other hand, the so-called latent autoimmune diabetes of the adult (LADA) is a slowly progressive form of adult-onset autoimmune diabetes that is noninsulin-dependent at the time of clinical diagnosis and is characterized by the presence of glutamic acid decarboxylase-65 (GAD65: 138275) autoantibodies and/or islet cell antibodies. </p>
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<strong>Biochemical Features</strong>
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<p>Nepom et al. (1987) studied the mechanism of the exaggerated susceptibility to IDDM in DR3/DR4 heterozygotes, and concluded that its basis is the formation of hybrid molecules of the closely linked DQ-alpha (HLA-DQA1; 146880) and -beta (HLA-DQB1; 604305) chains. The DR-alpha molecules are not polymorphic, and mixed DR alpha-beta dimers would not result in novel HLA molecules. On the other hand, both the alpha and beta chains of DQ are polymorphic, and a DQ alpha-beta dimer composed of transcomplementing chains would be unique to a heterozygous individual and not expressed in either parent. In the mouse, such transcomplementation has been demonstrated structurally, and epitopes newly formed in the resulting hybrid molecules allow for an altered functional immune response different from that of either parent. </p><p>The human MHC class II molecule encoded by DQA1*0102/DQB1*0602 (termed DQ0602) confers strong susceptibility to narcolepsy (161400) but dominant protection against type 1 diabetes. To elucidate the molecular features underlying these contrasting genetic properties, Siebold et al. (2004) determined the crystal structure of the DQ0602 molecule at 1.8-angstrom resolution. Structural comparisons to homologous DQ molecules with differential disease associations highlighted a previously unrecognized interplay between the volume of the P6 pocket and the specificity of the P9 pocket, which implies that presentation of the expanded peptide repertoire is critical for dominant protection against type 1 diabetes. In narcolepsy, the volume of the P4 pocket appears central to the susceptibility, suggesting that the presentation of a specific peptide population plays a major role. </p>
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<strong>Other Features</strong>
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<p>Hyperglycemia, the basic metabolic abnormality in IDDM, is caused by abnormally increased gluconeogenesis and insufficient glucose disposal. Ketosis results from the accumulation of free fatty acids and their oxidation.</p><p>McCorry et al. (2006) found an association between IDDM and idiopathic generalized epilepsy (EIG; 600669) in a population-based survey in the U.K. Among 518 EIG patients aged 15 to 30 years, 7 also had IDDM. In contrast, there were 465 IDDM patients among an age-matched cohort of 150,000 individuals. The findings suggested that the prevalence of IDDM is increased in patients with EIG (odds ratio of 4.4). </p>
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<strong>Pathogenesis</strong>
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<p>Patients with type 1 diabetes have diminished responses following T-cell activation. By immunoblot analysis, Nervi et al. (2000) found reduced levels of phosphorylated CD3Z (186780) in IDDM1 patients after T-cell stimulation. Immunoblot, immunoprecipitation, and densitometric analyses revealed significantly reduced LCK expression in unstimulated peripheral blood cells of IDDM1 patients compared to controls. The reduced LCK expression correlated with a lower proliferative response. Very low LCK expression may also correlate with the HLA-DQB1*0201/0302 (see 604305) genotype. Confocal microscopy demonstrated normal plasma membrane expression of LCK in patients and controls. Downstream signal transducing molecules were not affected in these patients. </p><p>Kent et al. (2005) examined T cells from pancreatic draining lymph nodes, the site of islet cell-specific self-antigen presentation. They cloned single T cells in a nonbiased manner from pancreatic draining lymph nodes of patients with type 1 diabetes and from nondiabetic controls. A high degree of T-cell clonal expansion was observed in pancreatic lymph nodes from long-term diabetic patients but not from controls. The oligoclonally expanded T cells from diabetic patients with DR4, a susceptibility allele for type 1 diabetes, recognized the insulin A 1-15 epitope restricted by DR4. Kent et al. (2005) concluded that their results identified insulin-reactive, clonally expanded T cells from the site of autoinflammatory drainage in long-term type 1 diabetics, indicating that insulin may indeed be the target antigen causing autoimmune diabetes. </p><p>Porter and Barrett (2005) reviewed monogenic syndromes of abnormal glucose homeostasis, focusing on 3 mechanisms: insulin resistance, insulin secretion defects, and beta-cell apoptosis. </p><p>Stechova et al. (2012) reported a family with naturally conceived monozygotic female quadruplets, in which type 1 diabetes was diagnosed in 2 of the quadruplets simultaneously and a third quadruplet was diagnosed as pre-diabetic. All 4 quadruplets were positive for anti-islet cell autoantibodies to GAD65 (138275) and to IA-2 (601773), indicating an ongoing anti-islet autoimmunity in the nondiabetic quadruplets. Serologic examination confirmed that all the quadruplets and their father had recently undergone an enteroviral infection of the EV68-81 serotype. Immunocompetent cells from all family members were characterized by gene expression arrays, immune-cell enumerations, and cytokine-production assays. The microarray data provided evidence that the viral infection and IL27 (608273) and IL9 (146931) cytokine signaling contributed to the onset of T1D in 2 of the quadruplets. Stechova et al. (2012) stated that the propensity of stimulated immunocompetent cells from nondiabetic members of the family to secrete high levels of IFN-alpha (IFNA1; 147660) further corroborated their conclusion. They observed that the number of T-regulatory cells as well as plasmacytoid and/or myeloid dendritic cells was diminished in all family members. Stechova et al. (2012) concluded that this family supported the so-called 'fertile-field' hypothesis proposing that genetic predisposition to anti-islet autoimmunity, if 'fertilized' and precipitated by a viral infection, results in full-blown type 1 diabetes. </p>
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<strong>Inheritance</strong>
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<p>IDDM exhibits 30 to 50% concordance in monozygotic twins, suggesting that the disorder is dependent on environmental factors as well as genes. The average risk to sibs is 6% (Todd, 1990). Recessive, dominant, and multifactorial hypotheses have been advanced, as well as 'susceptibility' hypotheses (Rotter, 1981). Genetic and environmental influences in IDDM were reviewed by Craighead (1978). Usually in genetic disease the most severe form of a disorder shows the clearest genetic basis. It is therefore surprising to find that the genetics of IDDM is less clear than that of NIDDM. Concordance in NIDDM was 100% for identical twins in which the index case had onset of diabetes after age 45 years, and nearly half had a diabetic parent, while discordance was found in half the pairs with earlier onset, few of whom had a family history of diabetes (Tattersall and Pyke, 1972). </p><p>Nilsson (1964) commented on the difficulties of distinguishing dominant and recessive inheritance when gene frequency is high. He considered autosomal recessive inheritance of IDDM to be most likely, with a gene frequency of about 0.30 and a lifetime penetrance of about 70% for males and 90% for females. A gene frequency of about 0.05 and a penetrance of 25 to 30% would be required to account for the findings on a dominant hypothesis. Hodge et al. (1980) proposed a 3-allele model based on a susceptibility locus (S) tightly linked to the HLA complex. Thomson (1980) espoused a 2-locus model. See 125850 for a clear example of an autosomal dominant type of diabetes mellitus: maturity-onset diabetes of the young (MODY). </p><p>Cudworth and Woodrow (1975) found that the relative risk of IDDM was 2.12 for HLA-A 8 and 2.60 for W15. Rubinstein et al. (1977) found that diabetic sibs shared their HLA genes with a significantly increased frequency, leading them to postulate a recessive gene linked to HLA (and specifically to HLA-D as indicated by 3 informative cases with recombination within the HLA). They estimated the penetrance at 50% because half the HLA-identical sibs of index cases were diabetic. This conclusion fits with published observations of 6-10% risk to sibs of patients when both parents are normal. As an appendix to their paper, they presented a table of risk to relatives on the basis of the above hypotheses. Barbosa et al. (1978) also concluded that IDDM is a recessive with 50% penetrance and with linkage to HLA (theta = 0.13, lod = 3.98) on the basis of the study of 21 families with 2 or more affected sibs and normal parents. </p><p>Vadheim et al. (1986) pointed out that several studies suggested a higher incidence of IDDM among the offspring of affected males than among those of affected females. To test the hypothesis that differential transmission by the father of genes predisposed to diabetes may explain this phenomenon, Vadheim et al. (1986) examined parent-to-offspring transmission of HLA haplotypes and DR alleles in 107 nuclear families in which a child had IDDM. They found that fathers with a DR4 allele were significantly more likely to transmit this allele to their diabetic or nondiabetic children than were mothers with a DR4 allele. No difference between parents was observed for HLA-DR3; however, DR3 was transmitted significantly more than 50% of the time from either parent. Field et al. (1986) reconfirmed the fact that sharing of 2 HLA haplotypes by sibs with diabetes mellitus was increased in comparison to mendelian expectations. Whereas sharing of GM-region genes was not different from mendelian expectations in the total sampled, affected pairs who shared 2 HLA haplotypes did show significantly increased sharing of GM-region genes. </p><p>MacDonald et al. (1986) studied families with IDDM in parent and child. The proportion of diabetic parents who transmitted DR4 to diabetic offspring (78%) was significantly higher (P less than 0.001) than the gene frequency of DR4 in the overall diabetic population (43%). The proportion of nondiabetic parents who transmitted DR4 to diabetic offspring (22%) was not significantly different from the gene frequency in the nondiabetic population but significantly lower (P less than 0.05) than the gene frequency in the overall IDDM population. This was taken to indicate a strong dominant effect of DR4. The proportion of nondiabetic parents who transmitted DR3 was similar to the gene frequency of DR3 in the overall diabetic population, but it was significantly higher than the gene frequency of DR 3 in the nondiabetic population (15%; P less than 0.005). The percentage of diabetic offspring who were DR3/DR4 (35%) was identical to that in the overall IDDM population (35%). MacDonald et al. (1986) interpreted this to mean that DR3 plays an enhancing role, with DR4 playing the main role. </p><p>Thomson et al. (1988) analyzed the results from 11 studies involving 1,792 Caucasian probands with IDDM. Antigen genotype frequencies in patients, transmission from affected parents to affected children, and the relative frequencies of HLA-DR3 and -DR4 homozygous patients all indicated that DR3 predisposes in a 'recessive'-like and DR4 in a 'dominant'-like or 'intermediate' fashion, after allowing for the synergistic effect of the 2 HLA types. DR2 showed a protective effect, DR1 and DRw8 showed predisposing effects, and DR5 showed a slight protective effect. They found evidence that only subsets of DR3 and DR4 are predisposing. The presence or absence of asp at position 57 of the DQ-beta gene was shown to be insufficient of itself in explaining the inheritance of IDDM. They suggested that the distinguishing features of the DR3-associated and DR4-associated predisposition remain to be identified at the molecular level. </p><p>Using an overall sib risk of 6%, Thomson et al. (1988) estimated that the risks for those sharing 2, 1, or 0 haplotypes are 12.9%, 4.5%, and 1.8%, respectively. The highest sib risk was 19.2% for sibs sharing 2 haplotypes with a DR3/DR4 proband. Field (1988) put this study in perspective with a discussion of other factors, including nongenetic factors. Sheehy et al. (1989) likewise concluded that susceptibility to diabetes is best defined by a combination of HLA-DR and HLA-DQ alleles. </p><p>In a study of 266 unrelated white patients with IDDM, Baisch et al. (1990) extended the assessment of the role of HLA-DQ alleles in susceptibility to the disease. They used allele-specific oligonucleotide probes and PCR to study HLA-DQ beta-chain alleles. Two major findings emerged. First, HLA-DQw1.2 was protective; it was found in only 2.3% of IDDM patients and in 36.4% of controls. This was 'dominant protection,' i.e., it did not matter what other allele was present. Second, HLA-DQw8 increased the risk of IDDM and the effect was one of 'dominant susceptibility' except that persons who were HLA-DQw1.2/DQw8 had a relative risk of 0.37, demonstrating that the protective effect of HLA-DQw1.2 predominated over the effect of HLA-DQw8. Segall and Bach (1990) reviewed the significance of these findings. See also review by Todd (1990). </p><p>The Eurodiab Ace Study Group and the Eurodiab Ace Substudy 2 Study Group (1998) studied the characteristics of familial type 1 diabetes mellitus, i.e., cases in which more than one affected first-degree relative was diagnosed before the age of 15 years. They used data from an international network of population-based registries and from a case-control study conducted in 8 of the network's centers. They found a positive association between the population incidence rate of type 1 diabetes and the prevalence of type 1 diabetes in fathers of affected children. A similar association was observed with the prevalence in sibs, but the association with prevalence in mothers was weaker and not significant. Pooling results from all centers showed that a greater proportion of fathers (3.4%) of affected children had type 1 diabetes than mothers (1.8%) giving a risk ratio of 1.8. Affected girls were more likely to have a father with type 1 diabetes than affected boys, but there was no evidence of a similar finding for mothers or sibs. Familial type 1 diabetes patients had a younger age at onset than nonfamilial patients. </p><p>Krischer et al. (2003) determined the extent to which different screening strategies could identify a population of nondiabetic relatives of a proband with type 1 diabetes who had 2 or more immunologic markers from the group consisting of islet cell antibodies (ICA), microinsulin autoantibodies (MIAA), GAD65 (138275) autoantibodies (GAA), and ICA512 (601773) autoantibodies (ICA512AA). Screening for any 3 antibodies guaranteed that all multiple antibody-positive subjects were detected. Screening for 2 antibodies at once and testing for the remaining antibodies among those who were positive for 1 resulted in a sensitivity of 99% for GAA and ICA, 97% for GAA and MIAA or GAA and ICA512AA, 93% for ICA512AA and ICA, 92% for MIAA and ICA, and 73% for ICA512AA and MIAA. From a laboratory perspective, screenings for GAA, ICA512AA, and MIAA are semiautomated tests with high throughput that, if used as initial screen, would identify at first testing 67% of the 2.3% of multiple antibody-positive relatives (100% if antibody-positive subjects are subsequently tested for ICA) as well as 4.7% of relatives with a single biochemical autoantibody, some of whom may convert to multiple autoantibody positivity on follow-up. Testing for ICA among relatives with 1 biochemical antibody would identify the remaining 33% of multiple antibody-positive relatives. They concluded that further follow-up and analysis of actual progression to diabetes will be essential to define actual diabetes risk in this large cohort. </p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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<span class="mim-text-font">
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<p><strong><em>General</em></strong></p><p>
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Clerget-Darpoux et al. (1981) concluded that the data in 30 multiplex families with IDDM best fitted a model with a susceptibility gene that was not linked to but interacted with the HLA system. Under 3 different genetic models for IDDM, Hodge et al. (1981) found evidence for linkage with 2 different sets of marker loci: HLA, properdin factor B, and glyoxalase-1 on chromosome 6, and Kidd blood group (then thought to be on chromosome 2, but later shown to be on chromosome 18). Thus, 2 distinct disease-susceptibility loci may be involved in IDDM, a situation also postulated for Graves disease (275000). </p><p>Bell et al. (1984) described an association between IDDM and a polymorphic region in the 5-prime flanking region of the insulin gene (INS; 176730). This polymorphism (Bell et al., 1981) arises from a variable number of tandemly repeated (VNTR) 14-bp oligonucleotides. When divided into 3 size classes, a significant association was seen between the short-length (class I) alleles and IDDM. Several studies were unable to demonstrate linkage of these VNTR alleles to IDDM in families, but this may in part be attributable to the fact that the disease-associated allele is present at high frequency in the general population. Several disease-associated polymorphisms were identified and the boundaries of association were mapped to a region of 19 kb on 11p15.5. Ferns et al. (1986) studied 14 families in which 13 had 2 cases of IDDM and found no linkage to polymorphic loci 5-prime to the insulin gene or to those 3-prime to the HRAS gene. Association with HLA was again found; persons who were HLA identical to the diabetic proband were more likely to be diabetic than those who were nonidentical. From studies of allele sharing in affected sib pairs, Cox et al. (1988) found evidence of HLA-linked susceptibility to IDDM but no evidence of a contribution of similar magnitude by the insulin-gene region. This failure of family studies to demonstrate linkage is difficult to reconcile with the association demonstrated between alleles at the VNTR locus in the 5-prime region of the insulin gene on 11p (Bell et al., 1984; Bell et al., 1985). Donald et al. (1989) used DR and DQ RFLPs for linkage analysis and demonstrated very close linkage of an IDDM-susceptibility locus. No evidence was found of any effect of the insulin gene. </p><p>Raum et al. (1979) found a rare genetic type of properdin factor B (F1) in 22.6% of patients with IDDM but in only 1.9% of the general population. If, as the authors suggested, this is an indication of linkage disequilibrium, not association, some populations should not show the relationship. </p><p>Based on a study in mice (Prochazka et al., 1987) it may be that corresponding recessive genes are located on chromosomes 6 and 11 in man; the THY1 (188230) and the APOA1 (107680) genes are on human 11q. By use of an affected sib pair method, Hyer et al. (1991) excluded the possibility of an IDDM susceptibility gene on 11q. </p><p>Lucassen et al. (1993) presented a detailed sequence comparison of the predominant haplotypes found in the region of 19 kb on 11p15.5 in a population of French-Canadian IDDM patients and controls. Identification of polymorphisms, both associated and unassociated with IDDM, permitted a further definition of the region of association to 4.1 kb. Ten polymorphisms within this region were found to be in strong linkage disequilibrium with each other and extended across the insulin gene locus and the VNTR situated immediately 5-prime to the insulin gene. These represent a set of candidate disease polymorphisms, one or more of which may account for the susceptibility to IDDM. </p><p>Using 96 affected sib pairs and a fluorescence-based linkage map of 290 marker loci (average spacing 11 cM), Davies et al. (1994) searched the human genome for genes that predispose to type 1 (insulin-dependent) diabetes mellitus. A total of 18 different chromosomal regions showed some positive evidence of linkage to the disease, strongly suggesting that IDDM is inherited in a polygenic fashion. Although the authors determined that no genes are likely to have as large effects as IDDM1 (in the major histocompatibility complex on 6p21), significant linkage was confirmed in the insulin gene region on 11p15 (IDDM2; 125852) and established to 11q (IDDM4; 600319), 6q (600320), and possibly to chromosome 18. Possible candidate genes within regions of linkage include GAD1 (605363) and GAD2 (138275), which encode the enzyme glutamic acid decarboxylase; SOD2 (147460), which encodes superoxide dismutase; and the Kidd blood group locus. Linkage of IDDM susceptibility to the region of the FGF gene on chromosome 11q13 was also reported by Hashimoto et al. (1994). </p><p>Genetic analysis of a mouse model of major histocompatibility complex-associated autoimmune type 1 (insulin-dependent) diabetes mellitus showed that the disease is caused by a combination of a major effect at the MHC and at least 10 other susceptibility loci elsewhere in the genome (Risch et al., 1993). </p><p>In a genomewide scan of 93 affected sib pair families from the UK, Davies et al. (1994) found a similar genetic basis for human type 1 diabetes, with a major component at the MHC locus (IDDM1) explaining 34% of the familial clustering of the disease. Mein et al. (1998) analyzed a further 263 multiplex families from the same population to provide a total UK dataset of 356 affected sib pair families. Only 4 regions of the genome outside IDDM1/MHC, which was still the only major locus detected, were not excluded, and 2 of these showed evidence of linkage: 10p13-p11 (maximum lod score = 4.7) and 16q22-q24 (maximum lod score = 3.4). They stated that these and other novel regions, including 14q12-q21 and 19p13-q13, could potentially harbor disease loci. </p><p>Concannon et al. (1998) reported the results of a genome screen for linkage with IDDM and analyzed the data by multipoint linkage methods. An initial panel of 212 affected sib pairs were genotyped for 438 markers spanning all autosomes, and an additional 467 affected sib pairs were used for follow-up genotyping. Other than the well-established linkage with the HLA region at 6p21.3, they found only 1 region, located on 1q and not previously reported, where the lod score exceeded 3.0. Lods between 1.0 and 1.8 were found in 6 other regions, 3 of which had been reported in other studies. </p><p>Cox et al. (2001) reported a genome scan using a new collection of 225 multiplex families with type 1 diabetes and combining the data with those from previous genome scans (Davies et al., 1994; Concannon et al., 1998; Mein et al., 1998). The combined sample of 831 affected sib pairs, all with both parents genotyped, provided 90% power to detect linkage. Three chromosome regions were identified that showed significant evidence of linkage with lod scores greater than 4: 6p21 (IDDM1); 11p15 (IDDM2); and 16q22-q24; 4 other regions showed suggestive evidence of linkage with lod scores of 2.2 or greater: 10p11 (IDDM10, 601942); 2q31 (IDDM7, 600321; IDDM12, 601388; IDDM13, 601318); 6q21 (IDDM15, 601666); and 1q42. Exploratory analyses, taking into account the presence of specific high-risk HLA genotypes or affected sibs' ages at disease onset, provided evidence of linkage at several additional sites, including the putative IDDM8 (600883) locus on 6q27. The results indicated that much of the difficulty in mapping type 1 diabetes susceptibility genes results from inadequate sample sizes, and pointed to the value of international collaborations to assemble and analyze much larger datasets for linkage in complex diseases. </p><p>Paterson and Petronis (2000) used data from a genomewide linkage study of 356 affected sib pairs with type 1 diabetes to perform linkage analyses using parental origin of shared alleles in subgroups based on sex of affected sibs and age of diagnosis. They found that evidence for linkage to IDDM4 occurred predominantly from opposite sex sib pairs and that for linkage to a locus on chromosome 4q occurred in sibs where one was diagnosed before age 10 years and one after age 10. Paterson and Petronis (2000) concluded that these methods might help reduce locus heterogeneity in type 1 diabetes. </p><p>Using DNA from 253 Danish IDDM families, Bergholdt et al. (2005) analyzed the chromosomal region 21q21.3-qter, which had been previously linked to IDDM by the European Consortium for IDDM Genome Studies (2001). Multipoint nonparametric linkage analysis showed a peak score of 3.61 at marker D21S1920 (p = 0.0002), and a '1-lod drop' interval of 6.3 Mb was identified between markers D21S261 and D21S270. No association was found with 74 coding SNPs from 32 candidate genes within the '1-lod drop' interval. </p><p>Using 2,360 SNP markers in the 4.4-Mb human major histocompatibility complex (MHC) locus and the adjacent 493 kb centromeric to the MHC, Roach et al. (2006) mapped the genetic influences for type 1 diabetes in 2 Swedish samples. They confirmed previous studies showing association with T1D in the MHC, most significantly near HLA-DR/DQ. In the region centromeric to the MHC, they identified a peak of association within the inositol 1,4,5-triphosphate receptor 3 gene (ITPR3; 147267). The most significant single SNP in this region was at the center of the ITPR3 peak of association. The estimated population-attributable risk of 21.6% suggested that variation within ITPR3 reflects an important contribution to T1D in Sweden. Two-locus regression analysis supported an influence of ITPR3 variation on T1D that is distinct from that of any MHC class II gene. </p><p>The Wellcome Trust Case Control Consortium (2007) described a joint genomewide association study using the Affymetrix GeneChip 500K Mapping Array Set, undertaken in the British population, which examined approximately 2,000 individuals and a shared set of approximately 3,000 controls for each of 7 major diseases. Case-control comparisons identified 7 independent association signals in type 1 diabetes at p values of less than 5.0 x 10(-7). </p><p>In a study of 4,000 individuals with type 1 diabetes, 5,000 controls, and 2,997 family trios independent of the Wellcome Trust Case Control Consortium (2007) study, Todd et al. (2007) confirmed the previously reported associations of rs2542151 in the PTPN2 gene (176887) on chromosome 18p11, rs17696736 in the C12ORF30 gene on chromosome 12q24, rs2292239 in the ERBB3 gene (190151) on chromosome 12q13, and rs12708716 in the KIAA0350 gene (CLEC16A; 611303) on chromosome 16p13 (p less than or equal to 10(-9); combined with WTCCC p less than or equal to 1.15 x 10(-14)), leaving 8 regions with small effects or false-positive associations. The association with rs17696736 led to the identification of a nonsynonymous SNP (rs3184504) in the SH2B3 gene (605093) that was sufficient to model the association of the entire region (p = 1.73 x 10(-21); see IDDM20, 612520). </p><p>To identify genetic factors that increase the risk of type 1 diabetes, Hakonarson et al. (2007) performed a genomewide association study in a large pediatric cohort of European descent. In addition to confirming previously identified loci, they found that type 1 diabetes was significantly associated with variation within a 233-kb linkage disequilibrium block on chromosome 16p13 that contains the KIAA0350 gene, which is predicted to encode a sugar-binding, C-type lectin. Three common noncoding variants of this gene (rs2903692, rs725613, and rs17673553) in strong linkage disequilibrium reached genomewide significance for association with type 1 diabetes. A subsequent transmission disequilibrium test replication study in an independent cohort confirmed the association. The combined P values for these SNPs ranged from 2.74 x 10(-5) to 6.7 x 10(-7). Hakonarson et al. (2007) noted that the Wellcome Trust Case Control Consortium (2007) had identified the KIAA0350 gene as a type 1 diabetes locus in a genomewide association study. </p><p>Smyth et al. (2008) evaluated the association between type 1 diabetes and 8 loci related to the risk of celiac disease in 8,064 patients with type 1 diabetes, 2,828 families providing 3,064 parent-child trios, and 9,339 controls. The authors found significant association between type 1 diabetes and rs1738074 in the TAGAP gene on chromosome 6q25 (see IDDM21, 612521) and confirmed association with rs3184504 in the SH2B3 gene (605093) on chromosome 12q24 (see IDDM20, 612520). </p><p>Cooper et al. (2008) performed a metaanalysis of 3 genomewide association studies, combining British type 1 diabetes (T1D) case-control data (Wellcome Trust Case Control Consortium, 2007) with T1D cases from the Genetics of Kidneys in Diabetes study (Mueller et al., 2006) for a total of 3,561 cases and 4,646 controls. Cooper et al. (2008) found support for a previously detected locus on chromosome 4q27 at rs17388568 (p = 1.87 x 10(-8); see IDDM23, 612622). After genotyping an additional 6,225 cases, 6,946 controls, and 2,828 families, they also found evidence for 4 previously unknown and distinct risk loci: at rs11755527 in intron 3 of the BACH2 gene (605394) on chromosome 6q15 (p = 4.7 x 10(-12)); at rs947474, near the PRKCQ gene (600448) on chromosome 10p15 (p = 3.7 x 10(-9)); at rs3825932 in intron 1 of the CTSH gene (116820) on chromosome 15q24 (p = 3.2 x 10(-15)); and at rs229541, located between the C1QTNF6 and SSTR3 (182453) genes on chromosome 22q13 (p = 2.0 x 10(-8)). </p><p>Barrett et al. (2009) reported the findings of a genomewide association study of type 1 diabetes, combined in a metaanalysis with 2 previously published studies (Wellcome Trust Case Control Consortium, 2007; Cooper et al., 2008). The total sample set included 7,514 cases and 9,045 reference samples. Forty-one distinct genomic locations provided evidence for association with type 1 diabetes in the metaanalysis (P less than 10(-6)). Using an analysis that combined comparisons over the 3 studies, they confirmed several previously reported associations, including rs2476601 at chromosome 1p13.2 (P = 8.5 x 10(-85)), rs7111341 at 11p15.5 (P = 4.4 x 10(-48)), rs2292239 at 12q13.2 (P = 2.2 x 10(-25)), and rs3184504 at 12q24.12 (P = 2.8 x 10(-27)). Barrett et al. (2009) further tested 27 novel regions in an independent set of 4,267 cases and 4,463 controls, and 2,319 affected sib pair families. Of these, 18 regions were replicated (P less than 0.01; overall P less than 5 x 10(-8)) and 4 additional regions provided nominal evidence of replication. A region on 1q32.1 represented by SNP rs3024505 (combined P = 1.9 x 10(-9)) contains the immunoregulatory cytokine genes IL10 (124092), IL19 (605687), and IL20 (605619). The strongest evidence of association among these 27 novel regions was achieved at rs10509540 on chromosome 10q23.31; see IDDM24, 613006. </p><p>Wallace et al. (2010) used imputation to assess association with T1D across 2.6 million SNPs in a total of 7,514 cases and 9,405 controls from 3 existing GWA studies (Wellcome Trust Case Control Consortium, 2007; Cooper et al., 2008; Barrett et al., 2009). They obtained evidence of an association at rs941576, a marker in the imprinted region of chromosome 14q32.2, for paternally inherited risk of T1D (p = 1.62 x 10(-10); ratio of allelic affects for paternal versus maternal transmissions = 0.75). Wallace et al. (2010) suggested that rs941576, which is located within intron 6 of the maternally expressed noncoding RNA gene MEG3 (605636), or another nearby variant alters the regulation of the neighboring functional candidate gene DLK1 (176290). </p><p>Inflammatory bowel disease (see 266600), including Crohn disease (CD) and ulcerative colitis (UC), and T1D are autoimmune diseases that may share common susceptibility pathways. Wang et al. (2010) examined known susceptibility loci for these diseases in a cohort of 1,689 CD cases, 777 UC cases, 989 T1D cases, and 6,197 shared control subjects of European ancestry. Multiple previously unreported or unconfirmed disease-loci associations were identified, including CD loci (ICOSLG, 605717; TNFSF15, 604052) and T1D loci (TNFAIP3; 191163) that conferred UC risk; UC loci (HERC2, 605837; IL26, 605679) that conferred T1D risk; and UC loci (IL10, 124092; CCNY, 612786) that conferred CD risk. T1D risk alleles residing at the PTPN22 (600716), IL27 (608273), IL18RAP (604509), and IL10 loci protected against CD. The strongest risk alleles for T1D within the major histocompatibility complex (MHC) conferred strong protection against CD and UC. The authors suggested that many loci involved in autoimmunity may be under a balancing selection due to antagonistic pleiotropic effects, and variants with opposite effects on different diseases may facilitate the maintenance of common susceptibility alleles in human populations. </p><p><strong><em>HLA Associations</em></strong></p><p>
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IDDM, although called the juvenile-onset type of diabetes, has its onset after the age of 20 years in 50% of cases. Caillat-Zucman et al. (1992) investigated whether the association of IDDM with certain HLA alleles, well-documented in pediatric patients, also holds for adults. Interestingly, they found quite different HLA class II gene profiles, with a significantly higher percentage of non-DR3/non-DR4 genotypes and a lower percentage of DR3/4 genotypes in older patients. Although the non-DR3/non-DR4 patients presented clinically as IDDM, they showed a lower frequency of islet cell antibodies (ICA) at diagnosis and a significantly milder insulin deficiency. These data (1) suggest these subjects probably represent a particular subset of IDDM patients in whom frequency increases with age; (2) confirm the genetic heterogeneity of IDDM; and (3) prompt caution in extrapolating the genetic concepts derived from childhood IDDM to adult patients. </p><p>Nerup et al. (1974) found that IDDM (but not NIDDM) is associated with 2 particular HLA-A types (142800)--HLA-A8 and W15. Woodrow and Cudworth (1975) interpreted the association of HLA-A8 and W15 with IDDM as resulting from linkage disequilibrium between genes for these antigens and a gene determining susceptibility of diabetes. </p><p>To test for linkage between HLA and a locus for susceptibility to this disease, Clerget-Darpoux et al. (1980) studied 28 informative families with at least 1 child suffering from juvenile-onset IDDM. The 28 families were pooled with 21 from the literature and autosomal recessive inheritance was assumed. Maximum lod scores (6.00 to 7.36) were obtained for recombination fractions from 4% to 16%, according to the level of assumed penetrance (from 90% down to 10%). These high estimates of the recombination fraction are not consistent with the hypothesis that the association between IDDM and specific HLA haplotypes is a consequence of simple linkage disequilibrium between HLA and a susceptibility locus. </p><p>Spielman et al. (1980) did HLA-typing on all members of 33 families in which 2 or more sibs had IDDM. They interpreted the results as supporting the hypothesis that, closely linked to the HLA region, there is a locus (symbolized S by them) for susceptibility to insulin-dependent diabetes. (S(d) was their symbol for the susceptibility allele and S(a) for all other alleles.) They estimated penetrance for the homozygote for S(d) to be 71% and for the heterozygote 6.5%. The recombination fraction between S and HLA was estimated to be under 3%. </p><p>Rubinstein et al. (1981) analyzed 3 sets of published data on HLA-typed families with IDDM in which no significant heterogeneity was detected. Autosomal recessive inheritance and incomplete penetrance were assumed. A maximum lod score of 7.40 at theta = 0.05 was found. The segregation of HLA and GLO in 5 affected sib pairs (4 of the 5 pairs were HLA-identical and GLO-different), in which one of the sibs carried an HLA-GLO recombinant, placed the IDDM locus closer to HLA than to GLO. </p><p>Dunsworth et al. (1982) performed complex segregation and linkage analysis in 182 families with at least 1 IDDM proband. All families were typed for HLA-B antigens and 118 for HLA-DR. The recessive model best fitted the data, with the maximum likelihood estimate of recombination between HLA-DR and the diabetes susceptibility factor being 0.019. Substantial heterogeneity was suggested; the smallest recombination was for families whose probands had 2 high-risk D alleles. Using RFLPs of the HLA-DR-alpha gene, Stetler et al. (1985) could show a higher association than is found with serologic markers. </p><p>Rich et al. (1987) studied linkage of IDDM with HLA and factor B (138470) in combination with segregation analysis. They found evidence of strong linkage disequilibrium with the B-BF-D haplotype, with IDDM probably tightly linked to HLA-DR. The recombination fraction between the postulated major locus for IDDM and HLA was 0 in all models. They concluded that the best fitting genetic model of diabetic susceptibility is that of a single major locus with 'near recessivity' on a scale of standardized genetic liability, with a gene frequency of the IDDM susceptibility allele of approximately 14%. </p><p>Julier et al. (1991) studied polymorphisms of INS and neighboring loci in random patients with diabetes, IDDM multiplex families, and controls. They found that HLA-DR4-positive diabetics showed an increased risk associated with common variants at polymorphic sites in a 19-kb segment spanned by the 5-prime INS VNTR and the third intron of the gene for insulin-like growth factor II (147470). In multiplex families the IDDM-associated alleles for polymorphisms in this region were transmitted preferentially to HLA-DR4-positive diabetic offspring from heterozygous parents. The effect was strongest in paternal meioses, suggesting a possible role for maternal imprinting. Julier et al. (1991) suggested that the results strongly support the existence of a gene or genes affecting HLA-DR4 IDDM susceptibility in a 19-kb region of INS-IGF2. Their approach may be useful in mapping susceptibility loci in other common diseases. </p><p>The fact that the association between IDDM and certain HLA-DQ alleles is even stronger than that with certain DR alleles and that there is little association with HLA-DP provides a boundary of disease association to the 430 kb between DQ and DP. In further studies of disease association with TAP (transporter associated with antigen processing) genes (170260), which map approximately midway between DP and DQ, Jackson and Capra (1993) found a higher association of a TAP allele with IDDM than with any single HLA-DP allele but the risk was lower than with HLA-DQB1*0302. These data provided new limits for IDDM susceptibility to the 190-kb interval between TAP1 and HLA-DQB1. </p><p>In a 2-stage approach to fine mapping, Herr et al. (2000) evaluated linkage in 385 affected sib-pair families using 13 evenly spaced polymorphic microsatellite markers spanning 14 Mb. Evidence of disease association was found for D6S2444, located within the 95% confidence interval of 1.7 cM obtained by linkage. Analysis of an additional 12 flanking markers revealed a highly specific region of 570 kb associated with disease that included the HLA class II genes. The peak of association was as close as 85 kb centromeric of HLA-DQB1. Recombination within the major histocompatibility complex was rare and nearly absent in the class III region. The authors concluded that the majority of disease association in the region can be explained by linkage disequilibrium with the class II susceptibility genes. </p><p>Greenbaum et al. (2000) noted that the presence of HLA haplotype DQA1*0102-DQB1*0602 is associated with protection from type 1 diabetes. The Diabetes Prevention Trial-type I has identified 100 islet cell antibody (ICA)-positive relatives with this protective haplotype, far exceeding the number of such subjects reported in other studies worldwide. Comparisons between ICA+ relatives with and without DQB1*0602 demonstrated no differences in gender or age; however, among racial groups, African American ICA+ relatives were more likely to carry this haplotype than others. The ICA+ DQB1*0602 individuals were less likely to have additional risk factors for diabetes (insulin autoantibody (IAA) positive or low first phase insulin release (FPIR)) than ICA+ relatives without DQB1*0602. However, 29% of the ICA+ DQB1*0602 relatives did have IAA or low FPIR. Hispanic ICA+ individuals with DQB1*0602 were more likely to be IAA positive or to have low FPIR than other racial groups. The authors conclude that the presence of ICA found in relatives suggests that whatever the mechanism that protects DQB1*0602 individuals from diabetes, it is likely to occur after the diabetes disease process has begun. In addition, they suggest that there may be different effects of DQB1*0602 between ethnic groups. </p><p>Redondo et al. (2000) used the transmission disequilibrium test to analyze haplotypes for association and linkage to diabetes within families from the Human Biological Data Interchange type I diabetes repository (1,371 subjects) and from the Norwegian Type 1 Diabetes Simplex Families study (2,441 subjects). DQA1*0102-DQB1*0602 was transmitted to 2 of 313 (0.6%) affected offspring (P less than 0.001, vs the expected 50% transmission). Protection was associated with the DQ alleles rather than DRB1*1501 in linkage disequilibrium with DQA1*0102-DQB1*0602: rare DRB1*1501 haplotypes without DQA1*0102-DQB1*0602 were transmitted to 5 of 11 affected offspring, whereas DQA1*0102-DQB1*0602 was transmitted to 2 of 313 affected offspring (P less than 0.0001). The authors concluded that both DR and DQ molecules (the DRB1*1401 and DQA1*0102-DQB1*0602 alleles) can provide protection from type IA diabetes. </p><p>Li et al. (2001) assessed the prevalence of families with both type 1 and type 2 diabetes in Finland and studied, in patients with type 2 diabetes, the association between a family history of type 1 diabetes, GAD antibodies (GADab), and type 1 diabetes-associated HLA-DQB1 genotypes. Further, in mixed type 1/type 2 diabetes families, they investigated whether sharing an HLA haplotype with a family member with type 1 diabetes influenced the manifestation of type 2 diabetes. Among 695 families with more than 1 patient with type 2 diabetes, 100 (14%) also had members with type 1 diabetes. Type 2 diabetic patients from the mixed families more often had GADab (18% vs 8%) and DQB1*0302/X genotype (25% vs 12%) than patients from families with only type 2 diabetes; however, they had a lower frequency of DQB1*02/0302 genotype compared with adult-onset type 1 patients (4% vs 27%). In the mixed families, the insulin response to oral glucose load was impaired in patients who had HLA class II risk haplotypes, either DR3(17)-DQA1*0501-DQB1*02 or DR4*0401/4-DQA1*0301-DQB1*0302, compared with patients without such haplotypes. This finding was independent of the presence of GADab. The authors concluded that type 1 and type 2 diabetes cluster in the same families. A shared genetic background with a patient with type 1 diabetes predisposes type 2 diabetic patients both to autoantibody positivity and, irrespective of antibody positivity, to impaired insulin secretion. Their findings also supported a possible genetic interaction between type 1 and type 2 diabetes mediated by the HLA locus. </p><p>Linkage data implicating other disease susceptibility loci for type 1 diabetes are conflicting. This is likely due to (1) the limited power for detection of contributions of additional susceptibility loci, given the limited number of informative families available for study; (2) factors such as genetic heterogeneity between populations; and (3) potential gene-gene and gene-environment interactions. To circumvent some of these problems, the European Consortium for IDDM Genome Studies (2001) conducted a genomewide linkage analysis for type 1 diabetes mellitus-susceptibility loci in 408 multiplex families from Scandinavia, a population expected to be homogeneous for genetic and environmental factors. In addition to verifying the HLA and INS susceptibility loci, the study confirmed the locus of IDDM15 (601666) on chromosome 6q21. Suggestive evidence of additional susceptibility loci was found on 2p, 5q, and 16p. For some loci, the support for linkage increased substantially when families were stratified on the basis of HLA or INS genotypes, with statistically significant heterogeneity between the stratified subgroups. These data support both the existence of non-HLA genes of significance for type 1 diabetes mellitus and the interaction between HLA and non-HLA loci in the determination of the type 1 diabetes mellitus phenotype. </p><p>Gambelunghe et al. (2001) estimated the frequency of major histocompatibility complex class I chain-related A gene (MICA; 600169) alleles and HLA-DRB1*03-DQA1*0501-DQB1*0201 and HLA-DRB1*04-DQA1*0301-DQB1*0302 in 195 type 1 diabetes mellitus subjects, in 80 latent autoimmune diabetes of the adult subjects, and in 158 healthy subjects from central Italy. The MICA5 allele was significantly associated with type 1 diabetes mellitus only in the group diagnosed before 25 years of age, and the odds ratio of the simultaneous presence of both the MICA5 allele and HLA-DRB1*03-DQA1*0501-DQB1*0201 and/or HLA-DRB1*04-DQA1*0301-DQB1*0302 was as high as 54 and higher than 388 when compared with double-negative individuals. Adult-onset type 1 diabetes mellitus (age at diagnosis greater than 25 years) and latent autoimmune diabetes of the adult were significantly associated with the MICA5.1 allele, which was not significantly increased among diabetic children. Only the combination of MICA5.1 and HLA-DRB1*03-DQA1*0501-DQB1*0201 and/or HLA-DRB1*04-DQA1*0301-DQB1*0302 conferred increased risk for adult-onset type 1 diabetes mellitus or for latent autoimmune diabetes of the adult. The authors concluded the existence of distinct genetic markers for childhood/young-onset IDDM and for adult-onset IDDM, namely the MICA5 and MICA5.1 alleles, respectively. </p><p>Qu and Polychronakos (2009) analyzed anti-IA-2 and anti-GAD65 autoantibody data from 2,282 type 1 diabetes patients from 1,117 multiplex families and found no association between anti-GAD65 (138275) autoantibodies and HLA. However, significant positive association was detected between anti-IA-2 (601773) autoantibodies and HLA-DRB1*0401, whereas negative association was detected with the DRB1*03-DQA1*0501-DQB1*0201 haplotype as well as with HLA-A*24, independent of the DRB1*03-DQA1*0501-DQB1*0201 haplotype. </p><p>The Wellcome Trust Case Control Consortium (2010) undertook a large direct genomewide study of association between copy number variants (CNVs) and 8 common human diseases. Using a purpose-designed array, they typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated 50% of all common CNVs greater than 500 basepairs. The Wellcome Trust Case Control Consortium (2010) identified several biologic artifacts that led to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed 3 loci where CNVs were associated with disease: HLA for Crohn disease (266600), rheumatoid arthritis (RA; 180300), and IDDM; IRGM (608282) for Crohn disease; and TSPAN8 (600769) for type 2 diabetes (125853). In each case the locus had previously been identified in SNP-based studies, reflecting the observation of The Wellcome Trust Case Control Consortium (2010) that most common CNVs that are well-typed on their array are well-tagged by SNPs and so have been indirectly explored through SNP studies. The Wellcome Trust Case Control Consortium (2010) concluded that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases. </p>
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<p>Todd et al. (1987) estimated that more than half of the inherited predisposition to IDDM maps to the region of the HLA class II genes on chromosome 6. Analysis of the DNA sequences from diabetics indicated that alleles of HLA-DQ(beta) determined both disease susceptibility and resistance. A non-asp at residue 57 of the beta-chain in particular confers susceptibility to IDDM and the autoimmune response against the insulin-producing islet cells. Morel et al. (1988) found that HLA haplotypes carrying an asp in position 57 of the DQ-beta chain (146880) were significantly increased in frequency among nondiabetics, while non-asp57 haplotypes were significantly increased in frequency among diabetics. Ninety-six percent of the diabetic probands were homozygous non-asp/non-asp as compared to 19.5% of healthy, unrelated controls. This represented a relative risk of 107 for non-asp57 homozygous individuals. See critique by Klitz (1988). </p><p>Khalil et al. (1990) presented evidence suggesting that asp57-negative DQ-beta as well as arg52-positive DQ-alpha chains are important to susceptibility to IDDM. Presumably, the modulation of susceptibility operates via the presentation of viral-antigenic peptide and/or autoantigen. I-Ag7, the only class II allele expressed by the nonobese diabetic mouse, lacks asp57. Corper et al. (2000) determined the crystal structure of the I-Ag7 molecule at 2.6-angstrom resolution as a complex with a high-affinity peptide from the autoantigen glutamic acid decarboxylase (GAD) 65 (138275). I-Ag7 has a substantially wider peptide-binding groove around beta-57, which accounts for distinct peptide preferences compared with other MHC class II alleles. Loss of asp-beta-57 leads to an oxyanion hole in I-Ag7 that can be filled by peptide carboxyl residues or, perhaps, through interaction with the T-cell receptor (see 186830). </p><p>Nakanishi et al. (1999) sought to identify IDDM-susceptible HLA antigens in IDDM patients who did not have the HLA-DQA1*0301 allele and to correlate the relationship of these HLA antigens to the degree of beta-cell destruction. In 139 Japanese IDDM patients and 158 normal controls, they typed HLA-A, -C, -B, -DR, and -DQ antigens. Serum C-peptide immunoreactivity response (delta-CPR) to a 100-g oral glucose load of 0.033 nmol/L or less was regarded as complete beta-cell destruction. All 14 patients without HLA-DQA1*0301 had HLA-A24, whereas only 35 of 58 (60.3%) normal controls without HLA-DQA1*0301 and only 72 of 125 (57.6%) IDDM patients with HLA-DQA1*0301 had this antigen (Pc of 0.0256 and 0.0080, respectively). Delta-CPR in IDDM patients with both HLA-DQA1*0301 and HLA-A24 was lower than in IDDM patients with HLA-DQA1*0301 only and in IDDM patients with HLA-A24 only. The authors concluded that both HLA-DQA1*0301 and HLA-A24 contribute susceptibility to IDDM independently and accelerate beta-cell destruction in an additive manner. </p><p>Donner et al. (1999) analyzed the presence of a solitary human endogenous retrovirus-K (HERV-K) long terminal repeat (LTR) in the HLA-DQ region (DQ-LTR3) and its linkage to DRB1, DQA1, and DQB1 haplotypes derived from 246 German and Belgian families with a patient suffering from IDDM. Segregation analysis of 984 HLA-DQA1/B1 haplotypes showed that DQ-LTR3 is linked to distinct DQA1 and DQB1 haplotypes but is absent in others. The presence of DQ-LTR3 on HLA-DQB1*0302 haplotypes was preferentially transmitted to patients from heterozygous parents (82%; P less than 10-6), in contrast to only 2 of 7 DQB1*0302 haplotypes without DQ-LTR3. Also, the extended HLA-DRB1*0401, DQB1*0302 DQ-LTR3-positive haplotypes were preferentially transmitted (84%; P less than 10-6) compared with 1 of 6 DR-DQ-matched DQ-LTR3-negative haplotypes. DQ-LTR3 is missing on most DQB1*0201 haplotypes, and those LTR3-negative haplotypes were also preferentially transmitted to patients (80%; P less than 10-6), whereas DQB1*0201 DQ-LTR3-positive haplotypes were less often transmitted to patients (36%). The authors concluded that the presence of DQ-LTR3 on HLA-DQB1*0302 and its absence on DQB1*0201 haplotypes are independent genetic risk markers for IDDM. </p><p>Pugliese et al. (1999) sequenced the DQB1*0602 and DQA1*0102 alleles in 8 ICA/DQB1*0602-positive relatives and in 6 rare patients with type 1 diabetes and DQB1*0602. They found that all relatives and patients carry the known DQB1*0602 and DQA1*0102 sequences, and none of them had the mtDNA 3243A-G mutation (590050.0001) associated with late-onset diabetes in ICA-positive individuals. Because they did not find diabetes in ICA/DQB1*0602-positive relatives, the authors concluded that the development of diabetes in individuals with DQB1*0602 remains very unlikely, even in the presence of ICA. </p><p>Cordell et al. (1995) applied to insulin-dependent diabetes mellitus an extension of the maximum lod score method of Risch (1990), which allowed the simultaneous detection and modeling of 2 unlinked disease loci. The method was applied to affected sib pair data, and the joint effects of IDDM1 (HLA) and IDDM2, the INS VNTR, and IDDM1 and IDDM4 (FGF3-linked) were assessed. In the presence of genetic heterogeneity, there seemed to be a significant advantage in analyzing more than 1 locus simultaneously. Cordell et al. (1995) stated that the effects at IDDM1 and IDDM2 were well described by a multiplicative genetic model, while those at IDDM1 and IDDM4 followed a heterogeneity model. </p><p>Cucca et al. (2001) predicted the protein structure of HLA-DQ by using the published crystal structures of different allotypes of the murine ortholog of DQ, IA. There were marked similarities both within and across species between type 1 diabetes protective class II molecules. Likewise, the type 1 diabetes predisposing molecules DR and murine IE showed conserved similarities that contrasted with the shared patterns observed between the protective molecules. There was also inter-isotypic conservation between protective DQ, IA allotypes, and protective DR4 subtypes. The authors proposed a model for a joint action of the class II peptide-binding pockets P1, P4, and P9 in disease susceptibility and resistance with a main role for P9 in DQ/IA and for P1 and P4 in DR/IE. They suggested shared epitope(s) in the target autoantigen(s) and common pathways in human and murine type 1 diabetes. </p><p>Kristiansen et al. (2003) demonstrated that the -174C variant of the -174G/C SNP in the IL6 gene (147620.0001) was significantly associated with IDDM in Danish females, but not in males, and that the association was not caused by preferential transmission distortion in females. Using reporter assay studies, they also demonstrated evidence suggesting that the repressed PMA-stimulated activity of the -174G variant was reverted by 17-beta-estradiol (E2), whereas the stimulated activity of the -174C variant was E2 insensitive and higher than the stimulated activity of the -174G variant in the absence of E2. Kristiansen et al. (2003) concluded that higher IL6 promoter activity may confer risk to IDDM in very young females and that this risk may be negated with increasing age, possibly by the increasing E2 levels in puberty. </p><p>Bottini et al. (2004) demonstrated association of a missense SNP in the PTPN22 gene (R620W; 600716.0001) with type 1 diabetes. Kawasaki et al. (2006) identified a promoter SNP in the PTPN22 gene (600716.0002) that associated with type 1 diabetes in Japanese and Korean IDDM patients. </p><p>Tessier et al. (2006) reported association of type 1 diabetes with 2 SNPs in the OAS1 gene (164350.0001, 164350.0002). </p><p>Smyth et al. (2008) identified a significant association between an insertion-deletion variant in the CCR5 gene on chromosome 3p21 (601373.0001) and a reduced risk for type 1 diabetes (IDDM22; 612522). </p><p>Concannon et al. (2009) reviewed the genetics of type 1A (immune-mediated) diabetes, noting that genes within the HLA region, predominantly those that encode antigen-presenting molecules, confer the greatest part of the genetic risk for type 1A diabetes. The authors concluded that the existence of other loci with individual effects on risk of a similar magnitude is very unlikely, and suggested that the remaining non-HLA loci will make only modest individual contributions to risk, with odds ratios of 1.3 or less. Concannon et al. (2009) noted that a majority of the other loci appear to exert their effects in the immune system, particularly on T cells. </p><p>Zalloua et al. (2008) identified homozygous or compound heterozygous mutations in the WFS1 gene (see, e.g., 606201.0024) in 22 (5.5%) of 399 Lebanese probands ascertained with juvenile-onset insulin-dependent diabetes, of whom 17 had Wolfram syndrome (WFS1; 222300) and 5 had nonsyndromic nonautoimmune diabetes mellitus. There were 2 additional probands who were given an initial diagnosis of nonsyndromic DM that was revised to WFS when they developed optic atrophy during the course of the study, and Zalloua et al. (2008) noted that longer follow-up of the nonsyndromic DM patients or a specific study of WFS adult patient populations would be needed to determine whether a subset of the WFS1-mutated nonsyndromic DM patients are exempted from extrapancreatic manifestations during their lifetime. </p><p>Santiago et al. (2008) genotyped the CAPSL (618799) SNPs rs1445898 and rs1010601 and 3 SNPs in the IL7R gene (rs6891932, rs987106, and rs3194051) in 301 unrelated Spanish type 1 diabetes patients and 646 healthy controls, and observed a trend towards a protective effect with the CAPSL SNP rs1445898. A similar trend for CAPSL rs1445898 was observed in 429 Dutch patients with type 1 diabetes compared to 720 healthy controls, and pooling the cohorts yielded a statistically significant difference (p = 0.005). The authors concluded that the CAPSL-IL7R locus is a protective region, but stated that they could not elucidate whether the protective gene was CAPSL, IL7R, or both. </p>
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<p>The diagnosis of type 1 diabetes is made on the basis of hyperglycemia with relative insulin deficiency with, or in the early stages without, ketosis in the absence of medications or conditions known to promote hyperglycemia.</p><p>In a study of an unselected population of 755 sibs of children with IDDM, Kulmala et al. (1998) evaluated the predictive value of islet cell antibodies, antibodies to the IA-2 protein, antibodies to the 65-kD isoform of GADA, insulin autoantibodies, and combinations of these markers. Within 7.7 years of the initial sample taken at or close to the diagnosis in the index case, 32 sibs progressed to IDDM. The positive predictive values of the 4 antibodies mentioned were 43%, 55%, 42%, and 29%, and their sensitivities 81%, 69%, 69%, and 25%, respectively. The final conclusion made by Kulmala et al. (1998) was that accurate assessment of the risk for IDDM in sibs is complicated, as not even all those with 4 antibody specificities contract the disease, and some with only 1 or no antibodies initially will progress to IDDM. </p><p>Kimpimaki et al. (2000) evaluated the emergence of diabetes-associated autoantibodies in young children and assessed whether such antibodies could be used as surrogate markers of type 1 diabetes in young subjects at increased genetic risk. They studied 180 initially unaffected sibs (92 boys and 88 girls) of children with newly diagnosed type 1 diabetes. All sibs were younger than 6 years of age at the initial sampling, and they were monitored for the emergence of islet cell antibodies (ICA), insulin autoantibodies (IAA), glutamate decarboxylase antibodies (GADA), and IA-2 antibodies (IA-2A) up to the age of 6 years and for progression to clinical type 1 diabetes up to the age of 10 years. Twenty-two sibs (12.2%) tested positive for ICA in their first antibody-positive sample before the age of 6 years, 13 (7.2%) tested positive for IAA, 15 (8.3%) tested positive for GADA, and 14 (7.8%) tested positive for IA-2A. There were 16 sibs (8.9%) who had 1 detectable autoantibody, 5 (2.8%) who had 2, and 12 (6.7%) who had 3 or more. These observations suggested to Kimpimaki et al. (2000) that disease-associated autoantibodies could be used as surrogate markers of clinical type 1 diabetes in primary prevention trials targeting young subjects with increased genetic disease susceptibility. </p><p>Wenzlau et al. (2007) identified type 1 diabetes autoantigen candidates from microarray expression profiling of human and rodent pancreas and islet cells, then screened the candidates with radioimmunoprecipitation assays using new-onset type 1 diabetes and prediabetic sera. The zinc transporter SLC30A8 (611145) was targeted by autoantibodies in 60 to 80% of new-onset type 1 diabetes compared with less than 2% of controls, less than 3% of patients with type 2 diabetes, and up to 30% of patients with other autoimmune disorders with a type 1 diabetes association. SLC30A8 antibodies were found in 26% of type 1 diabetics classified as autoantibody-negative on the basis of existing markers; the combined measurement of antibodies to SLC30A8, GADA, IA2, and insulin raised autoimmunity detection rates to 98% at disease onset. Wenzlau et al. (2007) concluded that SLC30A8 is a major autoantigen in type 1 diabetes. </p>
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<p>Clinical management of T1D requires use of dietary alterations and insulin therapy to maintain blood glucose levels within accepted range.</p><p>Lee et al. (2000) reported that a single-chain insulin analog (SIA) produced from the gene construct recombinant adeno-associated virus (AAV)-L-type pyruvate kinase (LPK)-SIA caused remission of diabetes in streptozotocin-induced diabetic rats and autoimmune diabetic mice for up to 8 months without any apparent side effects. Three of the authors retracted the paper in 2009 on the grounds that they had not been able to reproduce the results. </p><p>Cheung et al. (2000) found that gut K cells could be induced to produce human insulin by providing the cells with the human insulin gene linked to the 5-prime regulatory region of the gene encoding glucose-dependent insulinotropic polypeptide (GIP; 137240). Mice expressing this transgene produced human insulin specifically in gut K cells. This insulin protected the mice from developing diabetes and maintained glucose tolerance after destruction of the native insulin-producing beta cells. </p><p>Furuyama et al. (2019) showed that islet non-beta cells, namely alpha-cells and pancreatic polypeptide (PPY; 167780)-producing gamma cells, obtained from deceased nondiabetic or diabetic human donors, could be lineage-traced and reprogrammed by the transcription factors PDX1 (600733) and MAFA (610303) to produce and secrete insulin in response to glucose. When transplanted into diabetic mice, converted human alpha cells reversed diabetes and continued to produce insulin even after 6 months. Deep transcriptomic and proteomic characterization found that insulin-producing alpha cells maintained expression of alpha-cell markers. </p>
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<p>IDDM occurs about 20 times more frequently among children in the United States than among those in China. Bao et al. (1989) examined the question of whether this was due to a difference in the frequency of the allele leading to aspartic acid in position 57 of the HLA-DQ-beta chain. The presence of asp57 (or A) seems to protect against IDDM, while a noncharged amino acid in the same position (NA) is associated with increased susceptibility. Among probands in the IDDM registries in Allegheny County, Pa., 96% were homozygous NA, 4% were heterozygous, and none was homozygous A. In studies of 18 Chinese IDDM patients and 25 unrelated healthy Chinese controls, Bao et al. (1989) found that only 1 patient was homozygous NA and 13 were heterozygous, while among the 25 Chinese controls, 23 were homozygous A. The large proportion of homozygous A persons in the Chinese population is consistent with the low incidence of IDDM in China. The association between NA and IDDM may be strong in both populations. </p><p>Dorman et al. (1990) hypothesized that the 30-fold difference in IDDM incidence across racial groups and countries is related to variability in the frequency of NA alleles. To test the hypothesis, they evaluated diabetic and nondiabetic persons in 5 populations, with risks that were low, moderate, and high. NA alleles were significantly associated with IDDM in all areas, with population-specific odds ratios for NA homozygotes relative to A homozygotes ranging from 14 to 111. Dorman et al. (1990) used estimated genotype-specific incidence rates for Allegheny County, Pa., Caucasians to predict the overall incidence rates in the remaining populations. These predictions fell within the 95% confidence limits of the actual rates established from incidence registries. Results were considered consistent with the hypothesis that population variation in the distribution of NA alleles explains much of the geographic variation in IDDM incidence. Concannon et al. (1990) excluded close linkage of a gene making a major contribution to susceptibility to IDDM and the genes for 2 T-cell receptors, TCRA (see 186880) and TCRB (see 186930). </p><p>In a Japanese study, Imagawa et al. (2000) described what appeared to be a novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. Lernmark (2000) argued that, despite the unusual features, these patients had autoimmune type 1 diabetes. Since the patients described by Imagawa et al. (2000) had features of genetic susceptibility to autoimmune type 1 diabetes, Lernmark (2000) found it tempting to speculate that diabetes resulted from accelerated beta-cell destruction due to some environmental factor that had such a rapid effect that the autoimmune response characteristic of autoimmune type 1 diabetes was precluded. Along the same lines, Honeyman et al. (2000) suggested that rotavirus, which is not infectious until it is activated by trypsin (a product of the exocrine pancreas that can infect islets in tissue culture), may have been a cause of clinically silent pancreatic infection in the patients reported by Imagawa et al. (2000) and may have led to T cell-mediated loss of beta cells before islet-cell antibodies could develop. </p><p>The incidence of IDDM in Korea is less than one-tenth of that in the United States, and it has been suggested that HLA alleles of Asian patients associated with diabetes differ from those of Caucasians. Park et al. (2000) analyzed the common susceptibility and transmission pattern of a series of HLA DRB1-DQB1 haplotypes to Korean and Caucasian patients with IDDM. They performed HLA DR and DQ typing of 158 IDDM patients in a case control study, 140 nondiabetic subjects from the same geographic area, 49 simplex families from Seoul, and 283 families from the Human Biological Data Interchange. Although the haplotype frequencies in the 2 populations are quite different, when identical haplotypes are compared, their odds ratios are nearly the same. For all parental haplotypes, the transmission to diabetic offspring was similar for Korean and Caucasian families. The authors concluded that, not only by case-control comparison but also by transmission analyses of the haplotypes, that the susceptibility effects of DRB1-DQB1 haplotypes are consistent in Koreans and Caucasians. Thus, the influence of class II susceptibility and resistance alleles appears to transcend ethnic and geographic diversity of IDDM. </p>
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<p>Onodera et al. (1978) presented evidence that a single locus controls susceptibility to virus-induced diabetes mellitus in mice. They speculated that the gene might modulate expression of viral receptors on the beta cells of islets. DRw3 and DRw4 appear to be associated with JOD. The disease may be somewhat different depending on which is associated. The disease is more severe in homozygotes or genetic compounds (Bodmer, 1978). </p><p>Prochazka et al. (1987) established a polygenic basis for susceptibility to IDDM in nonobese diabetic mice (NOD) by outcross to a related inbred strain, nonobese normal. Analysis of first and second backcross progeny showed that at least 3 recessive genes are required for development of overt diabetes. One of them was tightly linked to the major histocompatibility complex on chromosome 17 of the mouse; a second was localized proximal to the Thy-1/Alp-1 cluster on mouse chromosome 9. (In an erratum, the authors stated that the original recombinant designation was erroneous.) It may be that corresponding recessive genes are located on chromosomes 6 and 11 in man; the THY1 (188230) and APOA1 (107680) genes are on human 11q. By use of an affected sib pair method, however, Hyer et al. (1991) appeared to have excluded the possibility of an IDDM susceptibility gene on 11q (see 125852). </p><p>Several features of the genetics and immunopathology of diabetes in the NOD mouse are closely similar to those of the human disease. Three murine diabetes susceptibility genes, Idd-1, Idd-3, and Idd-4, had been mapped, but only in the case of Idd-1 was there evidence concerning the identity of the gene product. Allelic variation within the murine immune response I-A(beta) gene and its human homolog, HLA-DQB1, correlated with susceptibility. Cornall et al. (1991) mapped Idd-5 to the proximal region of mouse chromosome 1. This region contains at least 2 candidate susceptibility genes: the interleukin-1 receptor gene (see 147810) and the Lsh/Ity/Bcg gene which encodes resistance to bacterial and parasitic infections and affects the function of macrophages (see 209950). </p><p>Garchon et al. (1991) demonstrated close association of periinsulitis in the NOD mouse with a locus on chromosome 1. In the NOD mouse, furthermore, insulitis and early-onset diabetes had been linked to chromosomes 3 and 11, respectively (Todd et al., 1991). Garchon et al. (1991) suggested that the existence of conserved syntenies between the human and murine genomes point to possible IDDM genes on human chromosomes 1, 2, or 18. </p><p>Overt type 1 diabetes is often preceded by the appearance of insulin autoantibodies. Furthermore, prophylactic administration of insulin to diabetes-prone rats, NOD mice, and human subjects results in protection from diabetes. These 2 observations suggest that an immune response to insulin is involved in the process of beta cell destruction in the pancreas. Daniel and Wegmann (1996) noted that islet-infiltrating cells isolated from NOD mice are enriched for insulin-specific T cells, insulin-specific T cell clones are capable of adoptive transfer of diabetes, and epitopes present on residues 9-23 of the B chain appear to be dominant in this spontaneous response. Against this background, Daniel and Wegmann (1996) tested the effect of either subcutaneous or intranasal administration of B-(9-23) on the incidence of diabetes in NOD mice. The results indicated to them that both modes of administration resulted in a marked delay in the onset and a decrease in the incidence of diabetes relative to mice given the control peptide, a tetanus toxin. The protective effect was associated with reduced T-cell proliferative response to B-(9-23) in B-(9-23)-treated mice. </p><p>Amrani et al. (2000) demonstrated that progression of pancreatic islet inflammation to overt diabetes in NOD mice is driven by the 'avidity maturation' of a prevailing, pancreatic beta-cell-specific T lymphocyte population carrying the CD8 antigen (186910). This T lymphocyte population recognizes 2 related peptides, NRP and NRP-A7, in the context of H-2K(d) class I molecules of the major histocompatibility complex. As prediabetic NOD mice age, their islet-associated CD8+ T lymphocytes contain increasing numbers of NRP-A7-reactive cells, and these cells bind NRP-A7/H-2K(d) tetramers with increased specificity, increased avidity, and longer half-lives. Repeated treatment of prediabetic NOD mice with soluble NRP-A7 peptide blunts the avidity maturation of the NRP-A7-reactive-CD8+ T cell population. This inhibits the local production of T cells that are cytotoxic to beta cells, and halts the progression from severe insulitis to diabetes. Amrani et al. (2000) concluded that avidity maturation of pathogenic T-cell populations may be the key event in the progression of benign inflammation to overt disease in autoimmunity. </p><p>Given the presence of islet beta-cell-reactive autoantibodies in prediabetic nonobese diabetic mice, Greeley et al. (2002) abrogated the maternal transmission of such antibodies in order to assess their influence on susceptibility of progeny to diabetes. First, they used B cell-deficient NOD mothers to eliminate the transmission of maternal immunoglobulins. In a complementary approach, they used immunoglobulin transgenic NOD mothers to exclude autoreactive specificities from the maternal B-cell repertoire. Finally, the authors implanted NOD embryos in pseudopregnant mothers of a nonautoimmune strain. In a commentary on the publication of Greeley et al. (2002), von Herrath and Bach (2002) noted that in the first experiment the incidence of diabetes was reduced to 25%, compared with 65% in offspring of B cell-competent mothers. The second experiment resulted in a more significant reduction: 20% of offspring developed diabetes versus 70% of offspring of nontransgenic mothers. In the third experiment, diabetes incidence was only 15% of offspring versus 73% of offspring of NOD mothers. Greeley et al. (2002) concluded that the maternal transmission of antibodies is a critical environmental parameter influencing the ontogeny of T cell-mediated destruction of islet beta cells in NOD mice. </p><p>Lang et al. (2005) investigated the circumstances under which CD8+ T cells specific for pancreatic beta islet antigens induce disease in mice expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) as a transgene under the control of the rat insulin promoter. In contrast to infection with LCMV, immunization with LCMV-GP-derived peptide did not induce autoimmune diabetes despite large numbers of autoreactive cytotoxic T cells; only subsequent treatment with Toll-like receptor (see 601194) ligands elicited overt diabetes. This difference was critically regulated by the pancreas itself, which upregulated class I major histocompatibility complex (MHC) in response to systemic Toll-like receptor-triggered interferon-alpha (147660) production. Lang et al. (2005) concluded that the 'inflammatory status' of the target organ is a separate and limiting factor determining the development of autoimmune disease. </p><p>The NOD mouse is not only the best model for spontaneous type 1 diabetes, but also for Sjogren syndrome (270150). In NOD mice, in which loss of salivary secretory function develops spontaneously (as in human Sjogren syndrome), Winer et al. (2002) found that disruption of the Ica69 gene (147625), which is expressed in salivary and lacrimal glands, prevented lacrimal gland disease and greatly reduced salivary gland disease. These animals developed type 1 diabetes with slight delay but at much the same incidence as wildtype animals, assigning a facultative rather than obligate role to ICA69 in the development of diabetes. </p><p>Nakayama et al. (2005) showed that the proinsulin/insulin molecules have a sequence that is a primary target of the autoimmunity that causes diabetes of the NOD mouse. They created insulin-1 and insulin-2 gene knockouts combined with a mutated proinsulin transgene, in which residue 16 on the B chain was changed to alanine, in NOD mice. This mutation abrogated the T-cell stimulation of a series of the major insulin autoreactive NOD T-cell clones. Female mice with only the altered insulin did not develop insulin autoantibodies, insulitis, or autoimmune diabetes, in contrast with mice containing at least 1 copy of the native insulin gene. Nakayama et al. (2005) suggested that proinsulin is a primary autoantigen of the NOD mouse and speculated that organ-restricted autoimmune disorders with marked major histocompatibility complex restriction of disease are likely to have specific primary autoantigens. </p><p>Treatment of NOD mice with end-stage disease by injection of donor splenocytes and complete Freund adjuvant eliminates autoimmunity and permanently restores normoglycemia. The return of endogenous insulin secretion is accompanied by the reappearance of pancreatic beta cells. Kodama et al. (2003) showed that live donor male or labeled splenocytes administered to diabetic NOD females contain cells that rapidly differentiate into islet or ductal epithelial cells within the pancreas. Treatment with irradiated splenocytes is also followed by islet regeneration, but at a slower rate. The islets generated in both instances are persistent, functional, and apparent in all NOD hosts with permanent disease reversal. </p><p>Chong et al. (2006), Nishio et al. (2006), and Suri et al. (2006) replicated the studies of Kodama et al. (2003). Chong et al. (2006) cured 32% of NOD mice of established diabetes (greater than 340 milligrams per deciliter blood glucose), although beta cells in these mice were not derived from donor splenocytes. Nishio et al. (2006) provided data indicating that the recovered islets were all of host origin, reflecting that the diabetic NOD mice actually retained substantial beta cell mass, which can be rejuvenated/regenerated to reverse disease upon adjuvant-dependent dampening of autoimmunity. Their study reported a 70% reversion rate to spontaneous diabetes among the treated animals compared to an 8% reversion rate in the study by Kodama et al. (2003). Suri et al. (2006) found that islet transplantation and immunization with Freund complete adjuvant along with multiple injections of allogeneic male splenocytes allowed for survival of transplanted islets and recovery of endogenous beta-cell function in a proportion of mice, but with no evidence for allogeneic splenocyte-derived differentiation of new islet beta cells. Suri et al. (2006) concluded that control of autoimmune disease at a crucial time in diabetogenesis can result in recovery of beta-cell function. </p><p>In a commentary on the papers of Chong et al. (2006), Nishio et al. (2006), and Suri and Unanue (2006), Faustman et al. (2006) stated that while these groups did not find that donor spleen cells contribute to the regeneration of the pancreas, Faustman et al. (2006) confirmed the results of Kodama et al. (2003) of a direct splenocyte contribution to insulin-expressing cells of the islets. In response to the comments by Faustman et al. (2006), Chong et al. (2006), Nishio et al. (2006), Suri and Unanue (2006) stated that they could not detect spleen cell transdifferentiation of spleen cells into beta cells in NOD mice. </p><p>Faustman (2007) refuted comments made by Nishio et al. (2006) that they did not use the appropriate controls. </p><p>Wen et al. (2008) showed that specific pathogen-free NOD mice lacking Myd88 (602170), an adaptor for multiple innate immune receptors that recognize microbial stimuli, do not develop type 1 diabetes. The effect is dependent on commensal microbes because germ-free Myd88-negative NOD mice develop robust diabetes, whereas colonization of these germ-free Myd88-negative NOD mice with a defined microbial consortium (representing bacterial phyla normally present in human gut) attenuates type 1 diabetes. Wen et al. (2008) also found that Myd88 deficiency changes the composition of the distal gut microbiota, and that exposure to the microbiota of specific pathogen-free Myd88-negative NOD donors attenuates type 1 diabetes in germ-free NOD recipients. Wen et al. (2008) concluded that, taken together, their findings indicated that interaction of the intestinal microbes with the innate immune system is a critical epigenetic factor modifying type 1 diabetes predisposition. </p><p><strong><em>Reviews</em></strong></p><p>
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Tisch and McDevitt (1996) reviewed the molecular understanding of the pathogenesis of this autoimmune disease. Complete molecular understanding may permit the design of rational and effective means of prevention. Prevention could then replace insulin therapy, which is effective but associated with long-term renal, vascular, and retinal complications. They pointed to the concordance rate of only 50% in monozygotic twins, indicating as yet unidentified environmental factors. There is a north-south gradient in incidence of the disease, with the highest incidence in northern Europe (1% to 1.5% in Finland) and decreasing incidence in more southerly and tropical locations. Although this suggests the effect of infectious agents in the nonobese diabetic (NOD) mouse, germ-free NOD mice have the highest incidence (nearly 100%) that has been seen in any NOD colony. Tisch and McDevitt (1996) reviewed the role of the major histocompatibility complex, the autoantigens targeted in IDDM, the T-cell response in IDDM, and experience to date with immunotherapy. Even if safe, effective, and long-lasting immunotherapies are developed, their application presents a formidable challenge. Only 15% of new cases of IDDM occur in families with a previous case. Overt diabetes develops only when beta cell destruction is nearly complete, and the patient is asymptomatic for months or years until that point is reached. Thus, immunotherapy must be preventive, which requires inexpensive and accurate genetic, autoantibody, and T cell screening techniques. </p><p>As indicated, linkage studies have shown that type 1 diabetes in NOD mice is a polygenic disease involving more than 15 chromosome susceptibility regions. Despite extensive investigation, the identification of individual susceptibility genes either within or outside the major histocompatibility complex region has proved problematic because of the limitations of linkage analysis. Hamilton-Williams et al. (2001) provided evidence implicating a single diabetes susceptibility gene that lies outside the MHC region, namely, beta-2-microglobulin (B2M; 109700). Using allelic reconstitution by transgenic rescue, they showed that NOD mice expressing the B2m*a allele developed diabetes, whereas NOD mice expressing a murine B2m*b or human allele of B2M were protected. The murine B2m*a allele differs from the B2m*b allele at only a single amino acid. Mechanistic studies indicated that the absence of the NOD B2m*a isoform on nonhematopoietic cells inhibited the development or activation of diabetogenic T cells. Hamilton-Williams et al. (2001) stated that it was not yet possible to determine whether subtle variations in B2M may also contribute to autoimmune diabetes in humans because the extent of polymorphism in this gene had not been extensively investigated. However, they noted that the B2m*a allele implicated as a dominant diabetes susceptibility gene in NOD mice is not a biologically aberrant variant but rather a common physiologically normal allele, which may exert its pathogenic functions only in certain combinatorial contexts. This supports the hypothesis of combinatorial context of 'normal' alleles (Nerup et al., 1994). They also noted that further support for this concept is strong linkage disequilibrium implicating a number of other physiologically normal cytokine variants as candidate susceptibility genes for diabetes (Lyons et al., 2000; Morahan et al., 2001); see 605998. </p><p>Vyse and Todd (1996) gave a general review of genetic analyses of autoimmune diseases, including this one. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>History</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using synalbumin insulin antagonism as a test, Vallance-Owen (1966) studied 9 families containing 16 overt cases of diabetes mellitus and concluded that the state of synalbumin positivity is a dominant. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>See Also:</strong>
|
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</span>
|
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</h4>
|
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<span class="mim-text-font">
|
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Adams et al. (1984); Barbosa et al. (1982); Creutzfeldt et al.
|
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(1976); Neel et al. (1965); Neel (1977); Pyke (1970); Renold et al.
|
|
(1972); Risch (1984); Rosenthal et al. (1976); Simpson (1964);
|
|
Steinberg et al. (1970); Suarez et al. (1978); Vinik et al. (1974);
|
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Zonana and Rimoin (1976)
|
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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Marla J. F. O'Neill - updated : 03/03/2020<br>Ada Hamosh - updated : 10/07/2019<br>George E. Tiller - updated : 9/16/2013<br>Marla J. F. O'Neill - updated : 5/10/2012<br>Marla J. F. O'Neill - updated : 9/22/2011<br>Ada Hamosh - updated : 4/28/2010<br>Marla J. F. O'Neill - updated : 4/19/2010<br>Marla J. F. O'Neill - updated : 1/29/2010<br>Marla J. F. O'Neill - updated : 10/12/2009<br>Ada Hamosh - updated : 9/8/2009<br>Marla J. F. O'Neill - updated : 4/28/2009<br>Ada Hamosh - updated : 4/16/2009<br>Marla J. F. O'Neill - updated : 2/11/2009<br>Ada Hamosh - updated : 11/26/2008<br>Marla J. F. O'Neill - updated : 3/20/2008<br>Marla J. F. O'Neill - updated : 11/9/2007<br>Ada Hamosh - updated : 8/13/2007<br>Ada Hamosh - updated : 7/31/2007<br>Ada Hamosh - updated : 7/19/2007<br>Marla J. F. O'Neill - updated : 2/26/2007<br>Ada Hamosh - updated : 1/25/2007<br>Victor A. McKusick - updated : 9/26/2006<br>Cassandra L. Kniffin - updated : 4/17/2006<br>Ada Hamosh - updated : 4/11/2006<br>Marla J. F. O'Neill - updated : 1/4/2006<br>Marla J. F. O'Neill - updated : 7/8/2005<br>Ada Hamosh - updated : 5/25/2005<br>Marla J. F. O'Neill - updated : 3/21/2005<br>George E. Tiller - updated : 2/23/2005<br>Victor A. McKusick - updated : 5/7/2004<br>John A. Phillips, III - updated : 2/9/2004<br>Ada Hamosh - updated : 12/3/2003<br>Victor A. McKusick - updated : 11/27/2002<br>Ada Hamosh - updated : 4/9/2002<br>John A. Phillips, III - updated : 3/14/2002<br>George E. Tiller - updated : 2/4/2002<br>Victor A. McKusick - updated : 12/20/2001<br>Victor A. McKusick - updated : 11/1/2001<br>Victor A. McKusick - updated : 10/23/2001<br>John A. Phillips, III - updated : 7/27/2001<br>John A. Phillips, III - updated : 7/11/2001<br>John A. Phillips, III - updated : 3/5/2001<br>Michael J. Wright - updated : 1/8/2001<br>Ada Hamosh - updated : 12/15/2000<br>Ada Hamosh - updated : 11/30/2000<br>Ada Hamosh - updated : 8/14/2000<br>John A. Phillips, III - updated : 8/10/2000<br>Victor A. McKusick - updated : 7/14/2000<br>George E. Tiller - updated : 6/30/2000<br>Ada Hamosh - updated : 4/20/2000<br>John A. Phillips, III - updated : 4/3/2000<br>Victor A. McKusick - updated : 2/7/2000<br>John A. Phillips, III - updated : 9/21/1999<br>Victor A. McKusick - updated : 2/27/1999<br>Victor A. McKusick - updated : 6/24/1998<br>Victor A. McKusick - updated : 3/25/1998
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Victor A. McKusick : 6/3/1986
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alopez : 01/25/2024<br>carol : 01/22/2024<br>carol : 09/04/2020<br>carol : 09/03/2020<br>carol : 04/08/2020<br>carol : 03/03/2020<br>carol : 10/08/2019<br>alopez : 10/07/2019<br>alopez : 08/12/2016<br>carol : 07/09/2016<br>carol : 4/8/2016<br>mgross : 10/4/2013<br>alopez : 9/16/2013<br>carol : 4/18/2013<br>terry : 4/1/2013<br>terry : 11/27/2012<br>terry : 8/31/2012<br>terry : 7/6/2012<br>carol : 5/10/2012<br>terry : 5/10/2012<br>carol : 9/23/2011<br>terry : 9/22/2011<br>wwang : 11/19/2010<br>terry : 11/12/2010<br>alopez : 11/11/2010<br>alopez : 11/10/2010<br>mgross : 9/3/2010<br>terry : 8/24/2010<br>alopez : 4/29/2010<br>terry : 4/28/2010<br>alopez : 4/22/2010<br>alopez : 4/22/2010<br>alopez : 4/21/2010<br>terry : 4/19/2010<br>carol : 2/4/2010<br>alopez : 1/29/2010<br>wwang : 10/29/2009<br>terry : 10/12/2009<br>alopez : 9/10/2009<br>alopez : 9/9/2009<br>terry : 9/8/2009<br>wwang : 7/29/2009<br>wwang : 5/6/2009<br>terry : 4/28/2009<br>alopez : 4/22/2009<br>terry : 4/16/2009<br>terry : 2/20/2009<br>carol : 2/13/2009<br>wwang : 2/12/2009<br>terry : 2/11/2009<br>carol : 1/7/2009<br>carol : 1/7/2009<br>alopez : 12/9/2008<br>terry : 11/26/2008<br>alopez : 8/28/2008<br>wwang : 3/25/2008<br>terry : 3/20/2008<br>wwang : 11/19/2007<br>terry : 11/9/2007<br>carol : 8/14/2007<br>terry : 8/13/2007<br>terry : 7/31/2007<br>alopez : 7/24/2007<br>terry : 7/19/2007<br>carol : 6/13/2007<br>wwang : 2/26/2007<br>alopez : 1/25/2007<br>terry : 1/25/2007<br>terry : 11/15/2006<br>alopez : 10/4/2006<br>terry : 9/26/2006<br>wwang : 4/24/2006<br>ckniffin : 4/17/2006<br>alopez : 4/11/2006<br>terry : 4/11/2006<br>alopez : 3/15/2006<br>wwang : 1/9/2006<br>terry : 1/4/2006<br>wwang : 7/20/2005<br>wwang : 7/15/2005<br>terry : 7/8/2005<br>wwang : 6/23/2005<br>wwang : 6/21/2005<br>tkritzer : 5/26/2005<br>terry : 5/25/2005<br>wwang : 3/23/2005<br>wwang : 3/21/2005<br>tkritzer : 3/7/2005<br>terry : 2/23/2005<br>alopez : 9/9/2004<br>carol : 5/25/2004<br>alopez : 5/17/2004<br>alopez : 5/17/2004<br>alopez : 5/17/2004<br>alopez : 5/17/2004<br>terry : 5/7/2004<br>carol : 3/17/2004<br>alopez : 2/9/2004<br>alopez : 12/8/2003<br>terry : 12/3/2003<br>tkritzer : 11/27/2002<br>alopez : 4/19/2002<br>cwells : 4/17/2002<br>cwells : 4/11/2002<br>terry : 4/9/2002<br>alopez : 3/14/2002<br>terry : 3/8/2002<br>cwells : 2/25/2002<br>cwells : 2/20/2002<br>cwells : 2/18/2002<br>cwells : 2/4/2002<br>alopez : 1/11/2002<br>cwells : 1/9/2002<br>terry : 12/20/2001<br>carol : 11/20/2001<br>mcapotos : 11/20/2001<br>mcapotos : 11/15/2001<br>terry : 11/1/2001<br>carol : 10/31/2001<br>mcapotos : 10/30/2001<br>terry : 10/23/2001<br>mgross : 7/27/2001<br>alopez : 7/11/2001<br>carol : 6/5/2001<br>alopez : 3/14/2001<br>alopez : 3/5/2001<br>mcapotos : 2/21/2001<br>alopez : 1/8/2001<br>mgross : 12/15/2000<br>terry : 12/15/2000<br>carol : 12/1/2000<br>terry : 11/30/2000<br>carol : 10/25/2000<br>alopez : 8/16/2000<br>terry : 8/14/2000<br>mgross : 8/10/2000<br>carol : 7/14/2000<br>terry : 7/14/2000<br>alopez : 6/30/2000<br>alopez : 4/20/2000<br>mgross : 4/19/2000<br>terry : 4/3/2000<br>mcapotos : 2/11/2000<br>terry : 2/7/2000<br>alopez : 12/3/1999<br>carol : 9/29/1999<br>mgross : 9/21/1999<br>jlewis : 6/25/1999<br>carol : 4/4/1999<br>carol : 2/27/1999<br>dkim : 12/9/1998<br>dkim : 7/24/1998<br>dholmes : 7/22/1998<br>alopez : 6/29/1998<br>terry : 6/24/1998<br>terry : 5/29/1998<br>alopez : 3/25/1998<br>terry : 3/19/1998<br>jenny : 7/2/1997<br>mark : 8/22/1996<br>terry : 8/21/1996<br>terry : 8/20/1996<br>terry : 8/19/1996<br>terry : 8/17/1996<br>mark : 8/15/1996<br>marlene : 8/6/1996<br>terry : 8/2/1996<br>mark : 2/9/1996<br>terry : 2/8/1996<br>mark : 12/13/1995<br>mark : 10/22/1995<br>terry : 6/24/1995<br>phil : 3/7/1995<br>carol : 1/23/1995<br>davew : 8/26/1994<br>mimadm : 4/26/1994
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