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Entry
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- #144250 - HYPERLIPIDEMIA, FAMILIAL COMBINED, 3; FCHL3
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- OMIM
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<span class="h4">#144250</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="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/144250"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#inheritance">Inheritance</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="#animalModel">Animal Model</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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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=(HYPERLIPIDEMIA, FAMILIAL COMBINED) OR (LPL)" class="mim-tip-hint" title="Clinical Trials" 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.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=21336&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/8593" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=144250[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><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=309015" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div style="display: table-cell;">Animal Models</div>
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</span>
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</span>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:13809" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/144250" 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/OMIA001210/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:13809" 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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<div style="display: table-cell;">Cell Lines</div>
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</a>
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:144250" 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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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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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> 238040008, 299465007<br />
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<strong>ICD10CM:</strong> E78.49<br />
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<strong>ORPHA:</strong> 309015<br />
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<strong>DO:</strong> 13809<br />
|
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">ICD+</a>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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144250
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</span>
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</span>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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HYPERLIPIDEMIA, FAMILIAL COMBINED, 3; FCHL3
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<div>
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<h4>
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<span class="mim-font">
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FAMILIAL COMBINED HYPERLIPIDEMIA
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</span>
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</h4>
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</div>
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<br />
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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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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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Gene/Locus
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Gene/Locus <br /> MIM number
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<tbody>
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<td>
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<span class="mim-font">
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<a href="/geneMap/8/91?start=-3&limit=10&highlight=91">
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8p21.3
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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Combined hyperlipidemia, familial
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</span>
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<td>
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<span class="mim-font">
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<a href="/entry/144250"> 144250 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</td>
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<td>
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<span class="mim-font">
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LPL
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/609708"> 609708 </a>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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<div>
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<div class="btn-group ">
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<a href="/clinicalSynopsis/144250" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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<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')">
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/144250" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/144250" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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<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>
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<div>
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<p />
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
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<div class="small" style="margin: 5px">
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<div>
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<span class="h5 mim-font">
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<strong> INHERITANCE </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
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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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<div>
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<span class="h5 mim-font">
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<strong> LABORATORY ABNORMALITIES </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Hyperlipidemia, mild, variable <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5232236&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5232236</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/55822004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">55822004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/166816003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">166816003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/3744001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">3744001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E78.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E78.5</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003077" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003077</a>]</span><br /> -
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Elevated serum cholesterol <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/166830008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">166830008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0595929&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0595929</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003124" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003124</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003124" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003124</a>]</span><br /> -
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Elevated triglycerides <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302870006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302870006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5200999&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5200999</a>, <a href="https://bioportal.bioontology.org/search?q=C0020557&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020557</a>]</span><br /> -
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Reduced HDL cholesterol <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5232237&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5232237</a>]</span><br />
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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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<div>
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<span class="h5 mim-font">
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<strong> MOLECULAR BASIS </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Susceptibility conferred by mutation in the lipoprotein lipase gene (LPL, <a href="/entry/609708#0033">609708.0033</a>)<br />
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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 class="text-right">
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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</div>
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</div>
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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="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div id="mimTextFold" class="collapse in ">
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because susceptibility to familial combined hyperlipidemia-3 (FCHL3) can be conferred by mutation in the LPL gene (<a href="/entry/609708">609708</a>) on chromosome 8p21.</p>
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</span>
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<br />
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<div>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>Familial combined hyperlipidemia (FCHL) is characterized by fluctuations in serum lipid concentrations and may present as mixed hyperlipidemia, isolated hypercholesterolemia, hypertriglyceridemia, or as a normal serum lipid profile in combination with abnormally elevated levels of apolipoprotein B (APOB; <a href="/entry/107730">107730</a>). Patients with FCHL are at increased risk of cardiovascular disease and mortality and have a high frequency of comorbidity with other metabolic conditions such as type 2 diabetes, nonalcoholic fatty liver disease, steatohepatitis, and the metabolic syndrome (summary by <a href="#5" class="mim-tip-reference" title="Bello-Chavolla, O. Y., Kuri-Garcia, A., Rios-Rios, M., Vargas-Vazquez, A., Cortes-Arroyo, J. E., Tapia-Gonzalez, G., Cruz-Bautista, I., Aguilar-Salinas, C. A. <strong>Familial combined hyperlipidemia: current knowledge, perspectives, and controversies.</strong> Rev. Invest. Clin. 70: 224-236, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30307446/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30307446</a>] [<a href="https://doi.org/10.24875/RIC.18002575" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30307446">Bello-Chavolla et al., 2018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30307446" 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="Goldstein, J. L., Schrott, H. G., Hazzard, W. R., Bierman, E. L., Motulsky, A. G. <strong>Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia.</strong> J. Clin. Invest. 52: 1544-1568, 1973.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4718953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4718953</a>] [<a href="https://doi.org/10.1172/JCI107332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4718953">Goldstein et al. (1973)</a> gave the designation 'familial combined hyperlipidemia' to the most common genetic form of hyperlipidemia identified in a study of survivors of myocardial infarction. Affected persons characteristically showed elevation of both cholesterol and triglycerides in the blood. The combined disorder was shown to be distinct from familial hypercholesterolemia (<a href="/entry/143890">143890</a>) and from familial hypertriglyceridemia (<a href="/entry/145750">145750</a>) for the following reasons: (1) lipid distributions in relatives were unique; (2) unlike familial hypercholesterolemia, children of affected persons did not express hypercholesterolemia; and (3) informative matings suggested that variable expression of a single gene rather than segregation for 2 separate genes was responsible. This disorder leads to elevated levels of VLDL, LDL, or both in plasma. From time to time the pattern can change in a given person. Unlike familial hypercholesterolemia, hyperlipidemia appears in only 10 to 20% of patients in childhood, usually in the form of hypertriglyceridemia. Xanthomas are rare. Increased production of VLDL may be a common underlying metabolic characteristic in this disorder, which may be heterogeneous. The disorder may be 5 times as frequent as familial hypercholesterolemia, occurring in 1% of the U.S. population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4718953" 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>Genetic Heterogeneity of Susceptibility to Familial Combined Hyperlipidemia</em></strong></p><p>
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Also see FCHL1 (<a href="/entry/602491">602491</a>), associated with variation in the USF1 gene (<a href="/entry/191523">191523</a>) on chromosome 1q23, and FCHL2 (<a href="/entry/604499">604499</a>), mapped to chromosome 11.</p>
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</span>
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<br />
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<a id="inheritance" class="mim-anchor"></a>
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<h4 href="#mimInheritanceFold" id="mimInheritanceToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimInheritanceToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Inheritance</strong>
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</span>
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</h4>
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<p>FCHL is an oligogenic primary lipid disorder, which can occur due to the interaction of several contributing variants and mutations along with environmental triggers (summary by <a href="#5" class="mim-tip-reference" title="Bello-Chavolla, O. Y., Kuri-Garcia, A., Rios-Rios, M., Vargas-Vazquez, A., Cortes-Arroyo, J. E., Tapia-Gonzalez, G., Cruz-Bautista, I., Aguilar-Salinas, C. A. <strong>Familial combined hyperlipidemia: current knowledge, perspectives, and controversies.</strong> Rev. Invest. Clin. 70: 224-236, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30307446/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30307446</a>] [<a href="https://doi.org/10.24875/RIC.18002575" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30307446">Bello-Chavolla et al., 2018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30307446" 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>FCHL was originally described as a disorder characterized by elevated levels of either plasma cholesterol or triglyceride (TG) or both in members of the same family (<a href="#15" class="mim-tip-reference" title="Goldstein, J. L., Schrott, H. G., Hazzard, W. R., Bierman, E. L., Motulsky, A. G. <strong>Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia.</strong> J. Clin. Invest. 52: 1544-1568, 1973.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4718953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4718953</a>] [<a href="https://doi.org/10.1172/JCI107332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4718953">Goldstein et al., 1973</a>). Using elevation of VLDL, LDL, or both as the phenotype in family studies, <a href="#15" class="mim-tip-reference" title="Goldstein, J. L., Schrott, H. G., Hazzard, W. R., Bierman, E. L., Motulsky, A. G. <strong>Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia.</strong> J. Clin. Invest. 52: 1544-1568, 1973.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4718953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4718953</a>] [<a href="https://doi.org/10.1172/JCI107332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4718953">Goldstein et al. (1973)</a> and <a href="#10" class="mim-tip-reference" title="Brunzell, J. D., Albers, J. J., Chait, A., Grundy, S. M., Groszek, E., McDonald, G. B. <strong>Plasma lipoproteins in familial combined hyperlipidemia and monogenic familial hypertriglyceridemia.</strong> J. Lipid Res. 24: 147-155, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6403642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6403642</a>]" pmid="6403642">Brunzell et al. (1983)</a> concluded that familial combined hyperlipidemia is an autosomal dominant trait with high penetrance. Homozygotes can show severe hypertriglyceridemia (<a href="#12" class="mim-tip-reference" title="Chait, A., Brunzell, J. D. <strong>Severe hypertriglyceridemia: role and familial and acquired disorders.</strong> Metabolism 32: 209-214, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6827992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6827992</a>] [<a href="https://doi.org/10.1016/0026-0495(83)90184-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6827992">Chait and Brunzell, 1983</a>). <a href="#11" class="mim-tip-reference" title="Brunzell, J. D., Schrott, H. G., Motulsky, A. G., Bierman, E. L. <strong>Myocardial infarction in the familial forms of hypertriglyceridemia.</strong> Metabolism 25: 313-320, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1250165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1250165</a>] [<a href="https://doi.org/10.1016/0026-0495(76)90089-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1250165">Brunzell et al. (1976)</a> estimated that 10% of premature coronary artery disease is caused by FCHL. Subsequently, studies (e.g., <a href="#10" class="mim-tip-reference" title="Brunzell, J. D., Albers, J. J., Chait, A., Grundy, S. M., Groszek, E., McDonald, G. B. <strong>Plasma lipoproteins in familial combined hyperlipidemia and monogenic familial hypertriglyceridemia.</strong> J. Lipid Res. 24: 147-155, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6403642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6403642</a>]" pmid="6403642">Brunzell et al., 1983</a>) indicated that apolipoprotein B levels (APOB; <a href="/entry/107730">107730</a>) were also elevated in these individuals. Although a dominant mode of inheritance was originally proposed, later studies questioned this simple mode of inheritance. The genetic basis of FCHL is apparently complex, with more than one genetic factor that can lead to this phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1250165+6403642+6827992+4718953" 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="#23" class="mim-tip-reference" title="Rauh, G., Schuster, H., Muller, B., Schewe, S., Keller, C., Wolfram, G., Zollner, N. <strong>Genetic evidence from 7 families that the apolipoprotein B gene is not involved in familial combined hyperlipidemia.</strong> Atherosclerosis 83: 81-87, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1975179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1975179</a>] [<a href="https://doi.org/10.1016/0021-9150(90)90133-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1975179">Rauh et al. (1990)</a> studied RFLPs of the apolipoprotein B gene (APOB; <a href="/entry/107730">107730</a>) in 33 unrelated persons with familial combined hyperlipidemia and in their families. No significant difference in allele frequency was found between the unrelated individuals and 107 normolipidemic controls. In the 33 families, 3 RFLP haplotypes were found to show no cosegregation with the phenotype of familial combined hyperlipidemia. These data were interpreted as inconsistent with the hypothesis that combined hyperlipidemia is caused by mutations of the APOB gene acting in a simple mendelian manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1975179" 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="#16" class="mim-tip-reference" title="Hayden, M. R., Kirk, H., Clark, C., Frohlich, J., Rabkin, S., McLeod, R., Hewitt, J. <strong>DNA polymorphisms in and around the Apo-AI-CIII genes and genetic hyperlipidemias.</strong> Am. J. Hum. Genet. 40: 421-430, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2883893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2883893</a>]" pmid="2883893">Hayden et al. (1987)</a> found an association between an XmnI RFLP and familial combined hyperlipidemia. The RFLP was located approximately 2.5 kb upstream of the APOA1 gene (<a href="/entry/107680">107680</a>). <a href="#29" class="mim-tip-reference" title="Wojciechowski, A. P., Farrall, M., Cullen, P., Wilson, T. M. E., Bayliss, J. D., Farren, B., Griffin, B. A., Caslake, M. J., Packard, C. J., Shepherd, J., Thakker, R., Scott, J. <strong>Familial combined hyperlipidaemia linked to the apolipoprotein AI-CIII-AIV gene cluster on chromosome 11q23-q24.</strong> Nature 349: 161-164, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1670899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1670899</a>] [<a href="https://doi.org/10.1038/349161a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1670899">Wojciechowski et al. (1991)</a> showed that the association between FCHL and the XmnI RFLP was the result of linkage disequilibrium between the disease and a 6.6-kb allele of the RFLP. Subsequent analysis in 7 FCHL families, ascertained through a proband carrying the 6.6-kb XmnI allele, demonstrated linkage to the AI-CIII-AIV cluster on 11q23-q24 (see <a href="/entry/107680">107680</a>); maximum lod score = 6.86 with no recombinants. The question remained as to where in the gene cluster the defect in this disorder resides. <a href="#29" class="mim-tip-reference" title="Wojciechowski, A. P., Farrall, M., Cullen, P., Wilson, T. M. E., Bayliss, J. D., Farren, B., Griffin, B. A., Caslake, M. J., Packard, C. J., Shepherd, J., Thakker, R., Scott, J. <strong>Familial combined hyperlipidaemia linked to the apolipoprotein AI-CIII-AIV gene cluster on chromosome 11q23-q24.</strong> Nature 349: 161-164, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1670899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1670899</a>] [<a href="https://doi.org/10.1038/349161a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1670899">Wojciechowski et al. (1991)</a> considered it unlikely that the mutation is in the APOA1 gene because the main reported effect of mutations in this gene had been lowering of HDL levels. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2883893+1670899" 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="Ito, Y., Azrolan, N., O'Connell, A., Walsh, A., Breslow, J. L. <strong>Hypertriglyceridemia as a result of human apo CIII gene expression in transgenic mice.</strong> Science 249: 790-793, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2167514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2167514</a>] [<a href="https://doi.org/10.1126/science.2167514" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2167514">Ito et al. (1990)</a> found that transgenic mice with the human APOC3 gene (<a href="/entry/107720">107720</a>) developed hypertriglyceridemia, and <a href="#26" class="mim-tip-reference" title="Tas, S. <strong>Strong association of a single nucleotide substitution in the 3-prime-untranslated region of the apolipoprotein-CIII gene with common hypertriglyceridemia in Arabs.</strong> Clin. Chem. 35: 256-259, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2914370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2914370</a>]" pmid="2914370">Tas (1989)</a> found a strong association between a single nucleotide substitution in the 3-prime untranslated region of the APOC3 gene with hypertriglyceridemia in Arabs. <a href="#30" class="mim-tip-reference" title="Xu, C.-F., Talmud, P., Schuster, H., Houlston, R., Miller, G., Humphries, S. <strong>Association between genetic variation at the APO AI-CIII-AIV gene cluster and familial combined hyperlipidaemia.</strong> Clin. Genet. 46: 385-397, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7889654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7889654</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1994.tb04404.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7889654">Xu et al. (1994)</a> reported evidence against linkage of FCHL to the AI-CIII-AIV gene region. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2914370+7889654+2167514" 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="Wijsman, E. M., Brunzell, J. D., Jarvik, G. P., Austin, M. A., Motulsky, A. G., Deeb, S. S. <strong>Evidence against linkage of familial combined hyperlipidemia to the apolipoprotein AI-CIII-AIV gene complex.</strong> Arterioscler. Thromb. Vasc. Biol. 18: 215-226, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9484986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9484986</a>] [<a href="https://doi.org/10.1161/01.atv.18.2.215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9484986">Wijsman et al. (1998)</a> performed linkage studies in 3 large pedigrees, previously ascertained for the study of severe hypertriglyceridemia (<a href="#12" class="mim-tip-reference" title="Chait, A., Brunzell, J. D. <strong>Severe hypertriglyceridemia: role and familial and acquired disorders.</strong> Metabolism 32: 209-214, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6827992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6827992</a>] [<a href="https://doi.org/10.1016/0026-0495(83)90184-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6827992">Chait and Brunzell, 1983</a>), using the same definitions and parameters as used in the report by <a href="#29" class="mim-tip-reference" title="Wojciechowski, A. P., Farrall, M., Cullen, P., Wilson, T. M. E., Bayliss, J. D., Farren, B., Griffin, B. A., Caslake, M. J., Packard, C. J., Shepherd, J., Thakker, R., Scott, J. <strong>Familial combined hyperlipidaemia linked to the apolipoprotein AI-CIII-AIV gene cluster on chromosome 11q23-q24.</strong> Nature 349: 161-164, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1670899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1670899</a>] [<a href="https://doi.org/10.1038/349161a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1670899">Wojciechowski et al. (1991)</a>. <a href="#28" class="mim-tip-reference" title="Wijsman, E. M., Brunzell, J. D., Jarvik, G. P., Austin, M. A., Motulsky, A. G., Deeb, S. S. <strong>Evidence against linkage of familial combined hyperlipidemia to the apolipoprotein AI-CIII-AIV gene complex.</strong> Arterioscler. Thromb. Vasc. Biol. 18: 215-226, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9484986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9484986</a>] [<a href="https://doi.org/10.1161/01.atv.18.2.215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9484986">Wijsman et al. (1998)</a> obtained strong evidence against linkage of FCHL to the apolipoprotein AI-CIII-AIV region on chromosome 11, with a combined lod score of -7.87 at 0% recombination. Other methods of analysis likewise excluded linkage. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6827992+9484986+1670899" 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>Small dense LDL particles are consistently associated with hypertriglyceridemia, premature coronary artery disease (CAD; see <a href="/entry/608320">608320</a>), and familial combined hyperlipidemia. In families 'enriched' for CAD, <a href="#21" class="mim-tip-reference" title="Nishina, P. M., Johnson, J. P., Naggert, J. K., Krauss, R. M. <strong>Linkage of atherogenic lipoprotein phenotype to the low density lipoprotein receptor locus on the short arm of chromosome 19.</strong> Proc. Nat. Acad. Sci. 89: 708-712, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1731344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1731344</a>] [<a href="https://doi.org/10.1073/pnas.89.2.708" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1731344">Nishina et al. (1992)</a> and <a href="#25" class="mim-tip-reference" title="Rotter, J. I., Bu, X., Cantor, R. M., Warden, C. H., Brown, J., Gray, R. J., Blanche, P. J., Krauss, R. M., Lusis, A. J. <strong>Multilocus genetic determinants of LDL particle size in coronary artery disease families.</strong> Am. J. Hum. Genet. 58: 585-594, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8644718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8644718</a>]" pmid="8644718">Rotter et al. (1996)</a> obtained evidence of linkage of the presence of small dense LDL particles with 4 separate candidate gene loci: the LDLR gene on 19p (<a href="/entry/606945">606945</a>), the apoAI-CIII-AIV gene cluster on 11q, the CETP (<a href="/entry/118470">118470</a>)/LCAT (<a href="/entry/606967">606967</a>) region of 16q, and the SOD2 locus on 6q (<a href="/entry/147460">147460</a>). <a href="#1" class="mim-tip-reference" title="Allayee, H., Aouizerat, B. E., Cantor, R. M., Dallinga-Thie, G. M., Krauss, R. M., Lanning, C. D., Rotter, J. I., Lusis, A. J., de Bruin, T. W. A. <strong>Families with familial combined hyperlipidemia and families enriched for coronary artery disease share genetic determinants for the atherogenic lipoprotein phenotype.</strong> Am. J. Hum. Genet. 63: 577-585, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9683614/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9683614</a>] [<a href="https://doi.org/10.1086/301983" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9683614">Allayee et al. (1998)</a> reported on a study that sought to test whether these same loci contribute to either LDL particle size or related phenotypes in families with FCHL. They found that SOD2, CETP/LCAT, and AI-CII-AIV loci exhibit evidence of linkage, whereas the LDLR locus failed to show significant evidence of linkage. Furthermore, the presence of small dense LDL particles was 10-fold greater in FCHL probands than in spouses, strengthening the frequently observed association between FCHL and the atherogenic lipoprotein phenotype (ALP; <a href="/entry/108725">108725</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9683614+1731344+8644718" 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 predominance of small dense LDL particles and elevated apolipoprotein B levels is commonly found in members of FCHL families. <a href="#9" class="mim-tip-reference" title="Bredie, S. J. H., Kiemeney, L. A., de Haan, A. F. J., Demacker, P. N. M., Stalenhoef, A. F. H. <strong>Inherited susceptibility determines the distribution of dense low-density lipoprotein subfraction profiles in familial combined hyperlipidemia.</strong> Am. J. Hum. Genet. 58: 812-822, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8644746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8644746</a>]" pmid="8644746">Bredie et al. (1996)</a> demonstrated a major gene effect on LDL particle size, and <a href="#8" class="mim-tip-reference" title="Bredie, S. J. H., Demacker, P. N. M., Stalenhoef, A. F. H. <strong>Metabolic and genetic aspects of familial combined hyperlipidaemia with emphasis on low-density lipoprotein heterogeneity.</strong> Europ. J. Clin. Invest. 27: 802-811, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9373757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9373757</a>] [<a href="https://doi.org/10.1046/j.1365-2362.1997.1850734.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9373757">Bredie et al. (1997)</a> demonstrated codominant mendelian inheritance involved in determination of apoB levels in a sample of 40 well-defined Dutch FCHL families. To establish whether a common gene regulates both traits, <a href="#18" class="mim-tip-reference" title="Juo, S.-H. H., Bredie, S. J. H., Kiemeney, L. A., Demacker, P. N. M., Stalenhoef, A. F. H. <strong>A common genetic mechanism determines plasma apolipoprotein B levels and dense LDL subfraction distribution in familial combined hyperlipidemia.</strong> Am. J. Hum. Genet. 63: 586-594, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9683593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9683593</a>] [<a href="https://doi.org/10.1086/301962" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9683593">Juo et al. (1998)</a> conducted a bivariate genetic analysis to test the hypothesis of a common genetic mechanism. They found that 66% of the total phenotypic correlation was due to shared genetic components. Further bivariate segregation analysis suggested that the 2 traits share a common major gene plus individual polygenic components. This common major gene explained 37% of the variance of adjusted LDL particle size and 23% of the variance of adjusted apoB levels. They suggested that a major gene that has pleiotropic effects on LDL particle size and apoB levels may be the gene underlying FCHL in the families they studied. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9373757+8644746+9683593" 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 a subset of 35 Dutch families ascertained for FCHL, <a href="#3" class="mim-tip-reference" title="Aouizerat, B. E., Allayee, H., Cantor, R. M., Davis, R. C., Lanning, C. D., Wen, P.-Z., Dallinga-Thie, G. M., de Bruin, T. W. A., Rotter, J. I., Lusis, A. J. <strong>A genome scan for familial combined hyperlipidemia reveals evidence of linkage with a locus on chromosome 11.</strong> Am. J. Hum. Genet. 65: 397-412, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10417282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10417282</a>] [<a href="https://doi.org/10.1086/302490" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10417282">Aouizerat et al. (1999)</a> screened the genome, with a panel of 399 genetic markers, for chromosomal regions linked to FCHL. The results were analyzed by parametric-linkage methods in a 2-stage study design. Suggestive evidence for linkage with FCHL (lod scores of 1.3 to 2.6) was found at 2p, 11p, 16q, and 19q. Markers within each of these regions were then examined in the original sample and in additional Dutch families with FCHL. The locus on chromosome 2 failed to show evidence for linkage, and the loci on 16q and 19q yielded only equivocal or suggestive evidence for linkage. However, 1 locus, near marker D11S1324 on 11p (HYPLIP2), continued to show evidence for linkage with FCHL in the second stage of the study. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10417282" 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 assess the genetic background of coronary heart disease by investigating the most common dyslipidemia predisposing to it, familial combined hyperlipidemia, <a href="#22" class="mim-tip-reference" title="Pajukanta, P., Allayee, H., Krass, K. L., Kuraishy, A., Soro, A., Lilja, H. E., Mar, R., Taskinen, M.-R., Nuotio, I., Laakso, M., Rotter, J. I., de Bruin, T. W. A., Cantor, R. M., Lusis, A. J., Peltonen, L. <strong>Combined analysis of genome scans of Dutch and Finnish families reveals a susceptibility locus for high-density lipoprotein cholesterol on chromosome 16q.</strong> Am. J. Hum. Genet. 72: 903-917, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12638083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12638083</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12638083[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/10.1086/374177" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12638083">Pajukanta et al. (2003)</a> combined data from genomewide screens performed in different study populations, the Finns and the Dutch. To perform a combined data analysis, they unified the diagnostic criteria for FCHL and its component traits. The pooled data analysis identified 3 chromosomal regions, on 2p25.1, 9p23, and 16q24.1, exceeding the statistical significance level of a lod score greater than 2.0. The 2p25.1 region was detected for the FCHL trait, and the 9p23 and 16q24.1 regions were detected for the low high-density lipoprotein-cholesterol (HDL-C) trait (see <a href="/entry/604091">604091</a>). Analysis of the 16q24.1 region resulted in a statistically significant lod score of 3.6 when the data from Finnish families with low HDL-C were included in the analysis. <a href="#22" class="mim-tip-reference" title="Pajukanta, P., Allayee, H., Krass, K. L., Kuraishy, A., Soro, A., Lilja, H. E., Mar, R., Taskinen, M.-R., Nuotio, I., Laakso, M., Rotter, J. I., de Bruin, T. W. A., Cantor, R. M., Lusis, A. J., Peltonen, L. <strong>Combined analysis of genome scans of Dutch and Finnish families reveals a susceptibility locus for high-density lipoprotein cholesterol on chromosome 16q.</strong> Am. J. Hum. Genet. 72: 903-917, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12638083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12638083</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12638083[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/10.1086/374177" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12638083">Pajukanta et al. (2003)</a> investigated the winged helix/forkhead transcription factor gene FOXC2 (<a href="/entry/602402">602402</a>) as a positional and functional candidate gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12638083" 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>Individuals heterozygous for lipoprotein lipase deficiency (<a href="/entry/238600">238600</a>) also show an FCHL phenotype. Indeed, a defect in the LPL gene may occur in up to a fifth of FCHL families (<a href="#4" class="mim-tip-reference" title="Babirak, S. P., Iverius, P.-H., Fujimoto, W. Y., Brunzell, J. D. <strong>Detection and characterization of the heterozygote state for lipoprotein lipase deficiency.</strong> Arteriosclerosis 9: 326-334, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2719595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2719595</a>] [<a href="https://doi.org/10.1161/01.atv.9.3.326" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2719595">Babirak et al., 1989</a>). One of 20 FCHL patients studied by <a href="#31" class="mim-tip-reference" title="Yang, W.-S., Nevin, D. N., Peng, R., Brunzell, J. D., Deeb, S. S. <strong>A mutation in the promoter of the lipoprotein lipase (LPL) gene in a patient with familial combined hyperlipidemia and low LPL activity.</strong> Proc. Nat. Acad. Sci. 92: 4462-4466, 1995. Note: Erratum: Proc. Nat. Acad. Sci. 93: 524 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7753827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7753827</a>] [<a href="https://doi.org/10.1073/pnas.92.10.4462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7753827">Yang et al. (1995)</a> was found to be compound heterozygous for mutations in the promoter region of the lipoprotein lipase gene (LPL; <a href="/entry/609708#0032">609708.0032</a> and <a href="/entry/609708#0038">609708.0038</a>), and most heterozygous parents of patients who are homozygous for the recessive disorder LPL deficiency (<a href="/entry/238600">238600</a>) have a lipid phenotype resembling that of mild FCHL. However, this recessive disorder, with an estimated carrier frequency of 0.2%, is too rare to account fully for the estimated prevalence of FCHL of 0.5 to 2%. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7753827+2719595" 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>Associations Pending Confirmation</em></strong></p><p>
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<a href="#13" class="mim-tip-reference" title="Geurts, J. M. W., Janssen, R. G. J. H., van Greevenbroek, M. M. J., van der Kallen, C. J. H., Cantor, R. M., Bu, X., Aouizerat, B. E., Allayee, H., Rotter, J. I., de Bruin, T. W. A. <strong>Identification of TNFRSF1B as a novel modifier gene in familial combined hyperlipidemia.</strong> Hum. Molec. Genet. 9: 2067-2074, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10958645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10958645</a>] [<a href="https://doi.org/10.1093/hmg/9.14.2067" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10958645">Geurts et al. (2000)</a> conducted a genomic scan in 18 Dutch FCHL families and identified several loci with evidence for linkage. Linear regression analysis using 79 independent sib pairs showed linkage with a quantitative FCHL discriminant function and the intron 4 (CA)n polymorphism of the tumor necrosis factor receptor 1B (TNFRSF1B; <a href="/entry/191191">191191</a>) (P = 0.032); a case-control study demonstrated an association as well (P = 0.029). Mutation analysis of exon 6 in 73 FCHL family members delineated 2 TNFRSF1B alleles, 1 coding for methionine (196M) and arginine (196R). Complete linkage disequilibrium between CA267, CA271, and CA273 and this polymorphism was detected. In 85 hyperlipidemic FCHL subjects, an association was demonstrated between soluble TNFRSF1B plasma concentrations and the CA271-196M haplotype. The authors concluded that TNFRSF1B is associated with susceptibility to FCHL. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10958645" 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="Allayee, H., Castellani, L. W., Cantor, R. M., de Bruin, T. W. A., Lusis, A. J. <strong>Biochemical and genetic association of plasma apolipoprotein A-II levels with familial combined hyperlipidemia.</strong> Circ. Res. 92: 1262-1267, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12738753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12738753</a>] [<a href="https://doi.org/10.1161/01.RES.0000075600.87675.16" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12738753">Allayee et al. (2003)</a> studied 18 extended families of Dutch Caucasian descent with familial combined hyperlipidemia and found that, despite having lower levels of HDL-C, FCHL subjects had higher apoA-II levels compared with unaffected relatives (p less than 0.00016). Triglyceride and HDL-C levels were significant predictors of apoA-II levels, demonstrating that apoA-II variation is associated with several FCHL-related traits. After adjustment for multiple covariates, there was evidence for the heritability of apoA-II levels (h-squared = 0.15; p less than 0.02) in this sample. A genome scan for apoA-II levels identified significant evidence (lod = 3.1) for linkage to a locus on chromosome 1q41, coincident with a suggestive linkage for triglycerides (lod = 1.4), suggesting that this locus may have pleiotropic effects on apoA-II and FCHL traits. <a href="#2" class="mim-tip-reference" title="Allayee, H., Castellani, L. W., Cantor, R. M., de Bruin, T. W. A., Lusis, A. J. <strong>Biochemical and genetic association of plasma apolipoprotein A-II levels with familial combined hyperlipidemia.</strong> Circ. Res. 92: 1262-1267, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12738753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12738753</a>] [<a href="https://doi.org/10.1161/01.RES.0000075600.87675.16" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12738753">Allayee et al. (2003)</a> concluded that apoA-II is biochemically and genetically associated with FCHL and may serve as a useful marker for understanding the mechanism by which FCHL develops. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12738753" 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="Brahm, A. J., Hegele, R. A. <strong>Combined hyperlipidemia: familial but not (usually) monogenic.</strong> Curr. Opin. Lipidol. 27: 131-140, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26709473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26709473</a>] [<a href="https://doi.org/10.1097/MOL.0000000000000270" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26709473">Brahm and Hegele (2016)</a> tabulated selected genes reported to be linked and/or associated with combined hyperlipidemia, along with the function of their proteins. The authors concluded that the genetic basis of FCHL includes a combination of occasional rare large-effect variants plus a high burden of common polymorphisms that in aggregate perturb an individual component of the combined phenotype. Expression of the combined phenotype is seen when genetic predisposition to both phenotypic components is strong and secondary factors are present. function of. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26709473" 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>Exclusion Studies</em></strong></p><p>
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In 10 well-defined Dutch patients with FCHL, <a href="#27" class="mim-tip-reference" title="van der Vleuten, G. M., Hijmans, A., Kluijtmans, L. A. J., Blom, H. J., Stalenhoef, A. F. H., de Graaf, J. <strong>Thioredoxin interacting protein in Dutch families with familial combined hyperlipidemia.</strong> Am. J. Med. Genet. 130A: 73-75, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15368498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15368498</a>] [<a href="https://doi.org/10.1002/ajmg.a.30036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15368498">van der Vleuten et al. (2004)</a> found no sequence variants in the coding region, 5-prime UTR, or introns of the TXNIP gene (<a href="/entry/606599">606599</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15368498" 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>Individuals with FCHL have large quantities of VLDL and LDL and develop premature coronary heart disease. <a href="#20" class="mim-tip-reference" title="Masucci-Magoulas, L., Goldberg, I. J., Bisgaier, C. L., Serajuddin, H., Francone, O. L., Breslow, J. L., Tall, A. R. <strong>A mouse model with features of familial combined hyperlipidemia.</strong> Science 275: 391-394, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8994037/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8994037</a>] [<a href="https://doi.org/10.1126/science.275.5298.391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8994037">Masucci-Magoulas et al. (1997)</a> created a mouse model displaying some of the features of FCHL by crossing mice carrying the human apolipoprotein C-III (APOC3; <a href="/entry/107720">107720</a>) transgene with mice deficient in the LDL receptor (LDLR; <a href="/entry/606945">606945</a>). A synergistic interaction between the apolipoprotein C-III and the LDLR defects resulted in large quantities of VLDL and LDL and enhanced the development of atherosclerosis. The authors commented that this mouse model may provide clues to the origin of human FCHL. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8994037" 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="#Bodnar2002" class="mim-tip-reference" title="Bodnar, J. S., Chatterjee, A., Castellani, L. W., Ross, D. A., Ohmen, J., Cavalcoli, J., Wu, C., Dains, K. M., Catanese, J., Chu, M., Sheth, S. S., Charugundla, K., Demant, P., West, D. B., de Jong, P., Lusis, A. J. <strong>Positional cloning of the combined hyperlipidemia gene Hyplip1.</strong> Nature Genet. 30: 110-116, 2002.">Bodnar et al. (2002)</a>; <a href="#Glueck1973" class="mim-tip-reference" title="Glueck, C. J., Fallat, R., Buncher, C. R., Tsang, R., Steiner, P. M. <strong>Familial combined hyperlipoproteinemia: studies in 91 adults and 95 children from 33 kindreds.</strong> Metabolism 22: 1403-1428, 1973.">Glueck et al. (1973)</a>; <a href="#Kissebah1984" class="mim-tip-reference" title="Kissebah, A. H., Alfarsi, S., Evans, D. J. <strong>Low density lipoprotein metabolism in familial combined hyperlipidemia: mechanism of the multiple lipoprotein phenotypic expression.</strong> Arteriosclerosis 4: 614-624, 1984.">Kissebah et al. (1984)</a>; <a href="#Rose1973" class="mim-tip-reference" title="Rose, H. G., Kranz, P., Weinstock, M., Juliano, J., Haft, J. I. <strong>Inheritance of combined hyperlipoproteinemia: evidence for a new lipoprotein phenotype.</strong> Am. J. Med. 54: 148-160, 1973.">Rose et al. (1973)</a>
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[<a href="https://doi.org/10.1086/301962" target="_blank">Full Text</a>]
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<a id="Kissebah1984" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1161/01.atv.4.6.614" target="_blank">Full Text</a>]
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<a id="Masucci-Magoulas1997" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1126/science.275.5298.391" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.89.2.708" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12638083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12638083</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12638083[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=12638083" 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/10.1086/374177" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1975179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1975179</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1975179" 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/10.1016/0021-9150(90)90133-4" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4346680/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4346680</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4346680" 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/10.1016/0002-9343(73)90218-0" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8644718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8644718</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8644718" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>Strong association of a single nucleotide substitution in the 3-prime-untranslated region of the apolipoprotein-CIII gene with common hypertriglyceridemia in Arabs.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2914370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2914370</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2914370" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="van der Vleuten2004" class="mim-anchor"></a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15368498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15368498</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15368498" 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/10.1002/ajmg.a.30036" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9484986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9484986</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9484986" 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/10.1161/01.atv.18.2.215" target="_blank">Full Text</a>]
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Wojciechowski, A. P., Farrall, M., Cullen, P., Wilson, T. M. E., Bayliss, J. D., Farren, B., Griffin, B. A., Caslake, M. J., Packard, C. J., Shepherd, J., Thakker, R., Scott, J.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1670899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1670899</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1670899" 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/10.1038/349161a0" target="_blank">Full Text</a>]
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Xu, C.-F., Talmud, P., Schuster, H., Houlston, R., Miller, G., Humphries, S.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7889654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7889654</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7889654" 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/10.1111/j.1399-0004.1994.tb04404.x" target="_blank">Full Text</a>]
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Yang, W.-S., Nevin, D. N., Peng, R., Brunzell, J. D., Deeb, S. S.
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<strong>A mutation in the promoter of the lipoprotein lipase (LPL) gene in a patient with familial combined hyperlipidemia and low LPL activity.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7753827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7753827</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7753827" 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.92.10.4462" target="_blank">Full Text</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 : 3/25/2014
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George E. Tiller - updated : 1/16/2007<br>Victor A. McKusick - updated : 12/2/2004<br>Marla J. F. O'Neill - updated : 3/18/2004<br>Marla J. F. O'Neill - updated : 2/19/2004<br>Victor A. McKusick - updated : 4/10/2003<br>George E. Tiller - updated : 11/17/2000<br>Victor A. McKusick - updated : 1/12/2000<br>Victor A. McKusick - updated : 3/15/1999<br>Victor A. McKusick - updated : 9/14/1998<br>Victor A. McKusick - updated : 4/1/1998<br>Victor A. McKusick - updated : 3/27/1998<br>Victor A. McKusick - updated : 6/27/1997
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Victor A. McKusick : 6/4/1986
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carol : 05/30/2019<br>alopez : 03/11/2015<br>carol : 3/27/2014<br>mcolton : 3/25/2014<br>terry : 9/4/2012<br>carol : 2/9/2011<br>alopez : 11/10/2010<br>carol : 4/21/2009<br>carol : 5/10/2007<br>alopez : 1/17/2007<br>terry : 1/16/2007<br>tkritzer : 12/2/2004<br>alopez : 4/2/2004<br>alopez : 3/18/2004<br>alopez : 3/18/2004<br>carol : 2/19/2004<br>carol : 4/11/2003<br>terry : 4/10/2003<br>ckniffin : 6/5/2002<br>ckniffin : 5/29/2002<br>mcapotos : 12/4/2000<br>mcapotos : 11/27/2000<br>terry : 11/17/2000<br>mgross : 2/4/2000<br>terry : 1/12/2000<br>terry : 1/12/2000<br>terry : 6/9/1999<br>carol : 3/19/1999<br>terry : 3/15/1999<br>carol : 9/17/1998<br>terry : 9/14/1998<br>alopez : 4/6/1998<br>terry : 4/1/1998<br>terry : 4/1/1998<br>terry : 3/27/1998<br>mark : 7/3/1997<br>terry : 6/27/1997<br>mimadm : 9/24/1994<br>carol : 11/12/1993<br>carol : 8/10/1993<br>supermim : 3/16/1992<br>carol : 2/6/1992<br>carol : 2/15/1991
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<strong>#</strong> 144250
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HYPERLIPIDEMIA, FAMILIAL COMBINED, 3; FCHL3
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<em>Alternative titles; symbols</em>
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FAMILIAL COMBINED HYPERLIPIDEMIA
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<strong>SNOMEDCT:</strong> 238040008, 299465007;
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<strong>ICD10CM:</strong> E78.49;
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<strong>ORPHA:</strong> 309015;
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<strong>DO:</strong> 13809;
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<strong>Phenotype-Gene Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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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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Gene/Locus
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Gene/Locus <br /> MIM number
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<span class="mim-font">
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8p21.3
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Combined hyperlipidemia, familial
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144250
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Autosomal dominant
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<span class="mim-font">
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3
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LPL
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609708
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because susceptibility to familial combined hyperlipidemia-3 (FCHL3) can be conferred by mutation in the LPL gene (609708) on chromosome 8p21.</p>
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<strong>Description</strong>
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<p>Familial combined hyperlipidemia (FCHL) is characterized by fluctuations in serum lipid concentrations and may present as mixed hyperlipidemia, isolated hypercholesterolemia, hypertriglyceridemia, or as a normal serum lipid profile in combination with abnormally elevated levels of apolipoprotein B (APOB; 107730). Patients with FCHL are at increased risk of cardiovascular disease and mortality and have a high frequency of comorbidity with other metabolic conditions such as type 2 diabetes, nonalcoholic fatty liver disease, steatohepatitis, and the metabolic syndrome (summary by Bello-Chavolla et al., 2018). </p><p>Goldstein et al. (1973) gave the designation 'familial combined hyperlipidemia' to the most common genetic form of hyperlipidemia identified in a study of survivors of myocardial infarction. Affected persons characteristically showed elevation of both cholesterol and triglycerides in the blood. The combined disorder was shown to be distinct from familial hypercholesterolemia (143890) and from familial hypertriglyceridemia (145750) for the following reasons: (1) lipid distributions in relatives were unique; (2) unlike familial hypercholesterolemia, children of affected persons did not express hypercholesterolemia; and (3) informative matings suggested that variable expression of a single gene rather than segregation for 2 separate genes was responsible. This disorder leads to elevated levels of VLDL, LDL, or both in plasma. From time to time the pattern can change in a given person. Unlike familial hypercholesterolemia, hyperlipidemia appears in only 10 to 20% of patients in childhood, usually in the form of hypertriglyceridemia. Xanthomas are rare. Increased production of VLDL may be a common underlying metabolic characteristic in this disorder, which may be heterogeneous. The disorder may be 5 times as frequent as familial hypercholesterolemia, occurring in 1% of the U.S. population. </p><p><strong><em>Genetic Heterogeneity of Susceptibility to Familial Combined Hyperlipidemia</em></strong></p><p>
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Also see FCHL1 (602491), associated with variation in the USF1 gene (191523) on chromosome 1q23, and FCHL2 (604499), mapped to chromosome 11.</p>
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<strong>Inheritance</strong>
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<p>FCHL is an oligogenic primary lipid disorder, which can occur due to the interaction of several contributing variants and mutations along with environmental triggers (summary by Bello-Chavolla et al., 2018). </p><p>FCHL was originally described as a disorder characterized by elevated levels of either plasma cholesterol or triglyceride (TG) or both in members of the same family (Goldstein et al., 1973). Using elevation of VLDL, LDL, or both as the phenotype in family studies, Goldstein et al. (1973) and Brunzell et al. (1983) concluded that familial combined hyperlipidemia is an autosomal dominant trait with high penetrance. Homozygotes can show severe hypertriglyceridemia (Chait and Brunzell, 1983). Brunzell et al. (1976) estimated that 10% of premature coronary artery disease is caused by FCHL. Subsequently, studies (e.g., Brunzell et al., 1983) indicated that apolipoprotein B levels (APOB; 107730) were also elevated in these individuals. Although a dominant mode of inheritance was originally proposed, later studies questioned this simple mode of inheritance. The genetic basis of FCHL is apparently complex, with more than one genetic factor that can lead to this phenotype. </p>
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<strong>Mapping</strong>
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<p>Rauh et al. (1990) studied RFLPs of the apolipoprotein B gene (APOB; 107730) in 33 unrelated persons with familial combined hyperlipidemia and in their families. No significant difference in allele frequency was found between the unrelated individuals and 107 normolipidemic controls. In the 33 families, 3 RFLP haplotypes were found to show no cosegregation with the phenotype of familial combined hyperlipidemia. These data were interpreted as inconsistent with the hypothesis that combined hyperlipidemia is caused by mutations of the APOB gene acting in a simple mendelian manner. </p><p>Hayden et al. (1987) found an association between an XmnI RFLP and familial combined hyperlipidemia. The RFLP was located approximately 2.5 kb upstream of the APOA1 gene (107680). Wojciechowski et al. (1991) showed that the association between FCHL and the XmnI RFLP was the result of linkage disequilibrium between the disease and a 6.6-kb allele of the RFLP. Subsequent analysis in 7 FCHL families, ascertained through a proband carrying the 6.6-kb XmnI allele, demonstrated linkage to the AI-CIII-AIV cluster on 11q23-q24 (see 107680); maximum lod score = 6.86 with no recombinants. The question remained as to where in the gene cluster the defect in this disorder resides. Wojciechowski et al. (1991) considered it unlikely that the mutation is in the APOA1 gene because the main reported effect of mutations in this gene had been lowering of HDL levels. </p><p>Ito et al. (1990) found that transgenic mice with the human APOC3 gene (107720) developed hypertriglyceridemia, and Tas (1989) found a strong association between a single nucleotide substitution in the 3-prime untranslated region of the APOC3 gene with hypertriglyceridemia in Arabs. Xu et al. (1994) reported evidence against linkage of FCHL to the AI-CIII-AIV gene region. </p><p>Wijsman et al. (1998) performed linkage studies in 3 large pedigrees, previously ascertained for the study of severe hypertriglyceridemia (Chait and Brunzell, 1983), using the same definitions and parameters as used in the report by Wojciechowski et al. (1991). Wijsman et al. (1998) obtained strong evidence against linkage of FCHL to the apolipoprotein AI-CIII-AIV region on chromosome 11, with a combined lod score of -7.87 at 0% recombination. Other methods of analysis likewise excluded linkage. </p><p>Small dense LDL particles are consistently associated with hypertriglyceridemia, premature coronary artery disease (CAD; see 608320), and familial combined hyperlipidemia. In families 'enriched' for CAD, Nishina et al. (1992) and Rotter et al. (1996) obtained evidence of linkage of the presence of small dense LDL particles with 4 separate candidate gene loci: the LDLR gene on 19p (606945), the apoAI-CIII-AIV gene cluster on 11q, the CETP (118470)/LCAT (606967) region of 16q, and the SOD2 locus on 6q (147460). Allayee et al. (1998) reported on a study that sought to test whether these same loci contribute to either LDL particle size or related phenotypes in families with FCHL. They found that SOD2, CETP/LCAT, and AI-CII-AIV loci exhibit evidence of linkage, whereas the LDLR locus failed to show significant evidence of linkage. Furthermore, the presence of small dense LDL particles was 10-fold greater in FCHL probands than in spouses, strengthening the frequently observed association between FCHL and the atherogenic lipoprotein phenotype (ALP; 108725). </p><p>A predominance of small dense LDL particles and elevated apolipoprotein B levels is commonly found in members of FCHL families. Bredie et al. (1996) demonstrated a major gene effect on LDL particle size, and Bredie et al. (1997) demonstrated codominant mendelian inheritance involved in determination of apoB levels in a sample of 40 well-defined Dutch FCHL families. To establish whether a common gene regulates both traits, Juo et al. (1998) conducted a bivariate genetic analysis to test the hypothesis of a common genetic mechanism. They found that 66% of the total phenotypic correlation was due to shared genetic components. Further bivariate segregation analysis suggested that the 2 traits share a common major gene plus individual polygenic components. This common major gene explained 37% of the variance of adjusted LDL particle size and 23% of the variance of adjusted apoB levels. They suggested that a major gene that has pleiotropic effects on LDL particle size and apoB levels may be the gene underlying FCHL in the families they studied. </p><p>Using a subset of 35 Dutch families ascertained for FCHL, Aouizerat et al. (1999) screened the genome, with a panel of 399 genetic markers, for chromosomal regions linked to FCHL. The results were analyzed by parametric-linkage methods in a 2-stage study design. Suggestive evidence for linkage with FCHL (lod scores of 1.3 to 2.6) was found at 2p, 11p, 16q, and 19q. Markers within each of these regions were then examined in the original sample and in additional Dutch families with FCHL. The locus on chromosome 2 failed to show evidence for linkage, and the loci on 16q and 19q yielded only equivocal or suggestive evidence for linkage. However, 1 locus, near marker D11S1324 on 11p (HYPLIP2), continued to show evidence for linkage with FCHL in the second stage of the study. </p><p>To assess the genetic background of coronary heart disease by investigating the most common dyslipidemia predisposing to it, familial combined hyperlipidemia, Pajukanta et al. (2003) combined data from genomewide screens performed in different study populations, the Finns and the Dutch. To perform a combined data analysis, they unified the diagnostic criteria for FCHL and its component traits. The pooled data analysis identified 3 chromosomal regions, on 2p25.1, 9p23, and 16q24.1, exceeding the statistical significance level of a lod score greater than 2.0. The 2p25.1 region was detected for the FCHL trait, and the 9p23 and 16q24.1 regions were detected for the low high-density lipoprotein-cholesterol (HDL-C) trait (see 604091). Analysis of the 16q24.1 region resulted in a statistically significant lod score of 3.6 when the data from Finnish families with low HDL-C were included in the analysis. Pajukanta et al. (2003) investigated the winged helix/forkhead transcription factor gene FOXC2 (602402) as a positional and functional candidate gene. </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<p>Individuals heterozygous for lipoprotein lipase deficiency (238600) also show an FCHL phenotype. Indeed, a defect in the LPL gene may occur in up to a fifth of FCHL families (Babirak et al., 1989). One of 20 FCHL patients studied by Yang et al. (1995) was found to be compound heterozygous for mutations in the promoter region of the lipoprotein lipase gene (LPL; 609708.0032 and 609708.0038), and most heterozygous parents of patients who are homozygous for the recessive disorder LPL deficiency (238600) have a lipid phenotype resembling that of mild FCHL. However, this recessive disorder, with an estimated carrier frequency of 0.2%, is too rare to account fully for the estimated prevalence of FCHL of 0.5 to 2%. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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Geurts et al. (2000) conducted a genomic scan in 18 Dutch FCHL families and identified several loci with evidence for linkage. Linear regression analysis using 79 independent sib pairs showed linkage with a quantitative FCHL discriminant function and the intron 4 (CA)n polymorphism of the tumor necrosis factor receptor 1B (TNFRSF1B; 191191) (P = 0.032); a case-control study demonstrated an association as well (P = 0.029). Mutation analysis of exon 6 in 73 FCHL family members delineated 2 TNFRSF1B alleles, 1 coding for methionine (196M) and arginine (196R). Complete linkage disequilibrium between CA267, CA271, and CA273 and this polymorphism was detected. In 85 hyperlipidemic FCHL subjects, an association was demonstrated between soluble TNFRSF1B plasma concentrations and the CA271-196M haplotype. The authors concluded that TNFRSF1B is associated with susceptibility to FCHL. </p><p>Allayee et al. (2003) studied 18 extended families of Dutch Caucasian descent with familial combined hyperlipidemia and found that, despite having lower levels of HDL-C, FCHL subjects had higher apoA-II levels compared with unaffected relatives (p less than 0.00016). Triglyceride and HDL-C levels were significant predictors of apoA-II levels, demonstrating that apoA-II variation is associated with several FCHL-related traits. After adjustment for multiple covariates, there was evidence for the heritability of apoA-II levels (h-squared = 0.15; p less than 0.02) in this sample. A genome scan for apoA-II levels identified significant evidence (lod = 3.1) for linkage to a locus on chromosome 1q41, coincident with a suggestive linkage for triglycerides (lod = 1.4), suggesting that this locus may have pleiotropic effects on apoA-II and FCHL traits. Allayee et al. (2003) concluded that apoA-II is biochemically and genetically associated with FCHL and may serve as a useful marker for understanding the mechanism by which FCHL develops. </p><p>Brahm and Hegele (2016) tabulated selected genes reported to be linked and/or associated with combined hyperlipidemia, along with the function of their proteins. The authors concluded that the genetic basis of FCHL includes a combination of occasional rare large-effect variants plus a high burden of common polymorphisms that in aggregate perturb an individual component of the combined phenotype. Expression of the combined phenotype is seen when genetic predisposition to both phenotypic components is strong and secondary factors are present. function of. </p><p><strong><em>Exclusion Studies</em></strong></p><p>
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In 10 well-defined Dutch patients with FCHL, van der Vleuten et al. (2004) found no sequence variants in the coding region, 5-prime UTR, or introns of the TXNIP gene (606599). </p>
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<p>Individuals with FCHL have large quantities of VLDL and LDL and develop premature coronary heart disease. Masucci-Magoulas et al. (1997) created a mouse model displaying some of the features of FCHL by crossing mice carrying the human apolipoprotein C-III (APOC3; 107720) transgene with mice deficient in the LDL receptor (LDLR; 606945). A synergistic interaction between the apolipoprotein C-III and the LDLR defects resulted in large quantities of VLDL and LDL and enhanced the development of atherosclerosis. The authors commented that this mouse model may provide clues to the origin of human FCHL. </p>
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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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<span class="mim-text-font">
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Bodnar et al. (2002); Glueck et al. (1973); Kissebah et al. (1984);
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Rose et al. (1973)
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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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<p />
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Allayee, H., Aouizerat, B. E., Cantor, R. M., Dallinga-Thie, G. M., Krauss, R. M., Lanning, C. D., Rotter, J. I., Lusis, A. J., de Bruin, T. W. A.
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<strong>Families with familial combined hyperlipidemia and families enriched for coronary artery disease share genetic determinants for the atherogenic lipoprotein phenotype.</strong>
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Am. J. Hum. Genet. 63: 577-585, 1998.
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[PubMed: 9683614]
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[Full Text: https://doi.org/10.1086/301983]
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Allayee, H., Castellani, L. W., Cantor, R. M., de Bruin, T. W. A., Lusis, A. J.
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<strong>Biochemical and genetic association of plasma apolipoprotein A-II levels with familial combined hyperlipidemia.</strong>
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Circ. Res. 92: 1262-1267, 2003.
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[PubMed: 12738753]
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[Full Text: https://doi.org/10.1161/01.RES.0000075600.87675.16]
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Contributors:
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Marla J. F. O'Neill - updated : 3/25/2014<br>George E. Tiller - updated : 1/16/2007<br>Victor A. McKusick - updated : 12/2/2004<br>Marla J. F. O'Neill - updated : 3/18/2004<br>Marla J. F. O'Neill - updated : 2/19/2004<br>Victor A. McKusick - updated : 4/10/2003<br>George E. Tiller - updated : 11/17/2000<br>Victor A. McKusick - updated : 1/12/2000<br>Victor A. McKusick - updated : 3/15/1999<br>Victor A. McKusick - updated : 9/14/1998<br>Victor A. McKusick - updated : 4/1/1998<br>Victor A. McKusick - updated : 3/27/1998<br>Victor A. McKusick - updated : 6/27/1997
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Victor A. McKusick : 6/4/1986
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carol : 05/30/2019<br>carol : 05/30/2019<br>alopez : 03/11/2015<br>carol : 3/27/2014<br>mcolton : 3/25/2014<br>terry : 9/4/2012<br>carol : 2/9/2011<br>alopez : 11/10/2010<br>carol : 4/21/2009<br>carol : 5/10/2007<br>alopez : 1/17/2007<br>terry : 1/16/2007<br>tkritzer : 12/2/2004<br>alopez : 4/2/2004<br>alopez : 3/18/2004<br>alopez : 3/18/2004<br>carol : 2/19/2004<br>carol : 4/11/2003<br>terry : 4/10/2003<br>ckniffin : 6/5/2002<br>ckniffin : 5/29/2002<br>mcapotos : 12/4/2000<br>mcapotos : 11/27/2000<br>terry : 11/17/2000<br>mgross : 2/4/2000<br>terry : 1/12/2000<br>terry : 1/12/2000<br>terry : 6/9/1999<br>carol : 3/19/1999<br>terry : 3/15/1999<br>carol : 9/17/1998<br>terry : 9/14/1998<br>alopez : 4/6/1998<br>terry : 4/1/1998<br>terry : 4/1/1998<br>terry : 3/27/1998<br>mark : 7/3/1997<br>terry : 6/27/1997<br>mimadm : 9/24/1994<br>carol : 11/12/1993<br>carol : 8/10/1993<br>supermim : 3/16/1992<br>carol : 2/6/1992<br>carol : 2/15/1991
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