3719 lines
319 KiB
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3719 lines
319 KiB
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Entry
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- #601367 - STROKE, ISCHEMIC
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- OMIM
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<p>
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<span class="h4">#601367</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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<li role="presentation">
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<a href="/clinicalSynopsis/601367"><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="#otherFeatures">Other Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#clinicalManagement">Clinical Management</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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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</a>
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</h4>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</a>
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<div class="panel-body small mim-panel-body">
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<div><a href="https://clinicaltrials.gov/search?cond=(STROKE, ISCHEMIC) OR (NOS3 OR F2 OR PRKCH OR ALOX5AP OR F5)" 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.diseaseinfosearch.org/x/8683" 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=601367[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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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</a>
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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:3526" 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/601367" 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://wormbase.org/resources/disease/DOID:3526" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</a>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" 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://catalog.coriell.org/Search?q=OmimNum:601367" 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 class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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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> 230690007, 422504002, 432504007<br />
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<strong>ICD10CM:</strong> I63, I63.9<br />
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<strong>DO:</strong> 3526<br />
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">ICD+</a>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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601367
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</span>
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</span>
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</div>
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</div>
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<div>
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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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STROKE, ISCHEMIC
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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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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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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CEREBROVASCULAR ACCIDENT<br />
|
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CEREBRAL INFARCTION
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/1/1404?start=-3&limit=10&highlight=1404">
|
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1q24.2
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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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{Stroke, ischemic, susceptibility to}
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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/601367"> 601367 </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="Multifactorial">Mu</abbr>
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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="3 - The molecular basis of the disorder is known"> 3 </abbr>
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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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<a href="/entry/601367"> 601367 </a>
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<a href="/entry/601367"> 601367 </a>
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ALOX5AP
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<a href="/entry/603700"> 603700 </a>
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14q23.1
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{Cerebral infarction, susceptibility to}
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<span class="mim-font">
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<a href="/entry/601367"> 601367 </a>
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<abbr class="mim-tip-hint" title="Multifactorial">Mu</abbr>
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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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<span class="mim-font">
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PRKCH
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<span class="mim-font">
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<a href="/entry/605437"> 605437 </a>
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<a href="/clinicalSynopsis/601367" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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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/601367" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/601367" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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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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<strong> Neuro </strong>
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- Stroke <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/230690007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">230690007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I63.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I63.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0038454&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0038454</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001297" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001297</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001297" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001297</a>]</span><br /> - Motor, sensory and/or cognitive function loss<br />
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<strong> Inheritance </strong>
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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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<p>A number sign (#) is used with this entry because common variants in several genes have been associated with increased susceptibility to development of ischemic stroke (see MOLECULAR GENETICS).</p><p>A locus for susceptibility to ischemic stroke has been mapped to chromosome 5q12 (STRK1; <a href="/entry/606799">606799</a>).</p><p>Several conditions in which stroke occurs are inherited in a classic mendelian pattern. As reviewed by <a href="#30" class="mim-tip-reference" title="Tournier-Lasserve, E. <strong>New players in the genetics of stroke.</strong> New Eng. J. Med. 347: 1711-1712, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12444190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12444190</a>] [<a href="https://doi.org/10.1056/NEJMcibr022035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12444190">Tournier-Lasserve (2002)</a>, these monogenic disorders have a low prevalence but a high risk for stroke in mutation carriers. The genes that have been identified include APP (<a href="/entry/104760">104760</a>), BRI (<a href="/entry/603904">603904</a>), and CST3 (<a href="/entry/604312">604312</a>), causing autosomal dominant amyloid angiopathies; NOTCH3 (<a href="/entry/600276">600276</a>), causing cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; <a href="/entry/125310">125310</a>); and KRIT1 (<a href="/entry/604214">604214</a>), causing cavernous angioma (<a href="/entry/116860">116860</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12444190" 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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<strong>Description</strong>
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<p>A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. It is said to be the third leading cause of death in the United States. <a href="#15" class="mim-tip-reference" title="Gunel, M., Lifton, R. P. <strong>Counting strokes.</strong> Nature Genet. 13: 384-385, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8696326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8696326</a>] [<a href="https://doi.org/10.1038/ng0896-384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8696326">Gunel and Lifton (1996)</a> noted that about 20% of strokes are hemorrhagic, resulting in bleeding into the brain. Ischemic strokes, resulting from vascular occlusion, account for the majority of strokes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8696326" 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="#4" class="mim-tip-reference" title="Bersano, A., Ballabio, E., Bresolin, N., Candelise, L. <strong>Genetic polymorphisms for the study of multifactorial stroke.</strong> Hum. Mutat. 29: 776-795, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18421701/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18421701</a>] [<a href="https://doi.org/10.1002/humu.20666" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18421701">Bersano et al. (2008)</a> reviewed genetic polymorphisms that have been implicated in the development of stroke. Candidate genes include those involved in hemostasis (see, e.g., F5; <a href="/entry/612309">612309</a>), the renin-angiotensin-aldosterone system (see, e.g., ACE; <a href="/entry/106180">106180</a>), homocysteine (see, e.g., MTHFR; <a href="/entry/607093">607093</a>), and lipoprotein metabolism (see, e.g., APOE; <a href="/entry/107741">107741</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18421701" 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>See also hemorrhagic stroke, or intracerebral hemorrhage (ICH; <a href="/entry/614519">614519</a>).</p>
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<p>Among 512 Korean patients with ischemic stroke, <a href="#2" class="mim-tip-reference" title="Bang, O. Y., Kim, J. W., Lee, J. H., Lee, M. A., Lee, P. H., Joo, I. S., Huh, K. <strong>Association of the metabolic syndrome with intracranial atherosclerotic stroke.</strong> Neurology 65: 296-298, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16043803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16043803</a>] [<a href="https://doi.org/10.1212/01.wnl.0000168862.09764.9f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16043803">Bang et al. (2005)</a> found a significant association between intracranial atherosclerotic stroke (143 patients) and components of the metabolic syndrome (AOMS1; <a href="/entry/605552">605552</a>), compared to those with extracranial atherosclerotic stroke (77 patients) and those with nonatherosclerotic stroke (292 patients). The association was particularly strong with regard to hypertension, abdominal obesity, and HDL cholesterol levels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16043803" 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="Campbell, D. J., Woodward, M., Chalmers, J. P., Colman, S. A., Jenkins, A. J., Kemp, B. E., Neal, B. C., Patel, A., MacMahon, S. W. <strong>Soluble vascular cell adhesion molecule 1 and N-terminal pro-B-type natriuretic peptide in predicting ischemic stroke in patients with cerebrovascular disease.</strong> Arch. Neurol. 63: 60-65, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16286536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16286536</a>] [<a href="https://doi.org/10.1001/archneur.63.1.noc50221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16286536">Campbell et al. (2006)</a> found that increased serum levels of soluble vascular adhesion molecule-1 (VCAM1; <a href="/entry/192225">192225</a>) predicted recurrent ischemic stroke in a study of 252 patients. A smaller but similar trend was noted for serum levels of N-terminal pro-B-type natriuretic peptide (NPPB; <a href="/entry/600295">600295</a>). Patients in the highest quarters for both sVCAM1 and NT-proBNP levels had 3.6 times the risk of recurrent ischemic stroke compared to patients in the lowest quarters for both biologic markers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16286536" 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>Among 195 nondemented stroke survivors over age 75 years who were followed for 2 years for cognitive decline and 5 years for survival, <a href="#23" class="mim-tip-reference" title="Martin-Ruiz, C., Dickinson, H. O., Keys, B., Rowan, E., Kenny, R. A., von Zglinicki, T. <strong>Telomere length predicts poststroke mortality, dementia, and cognitive decline.</strong> Ann. Neurol. 60: 174-180, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16685698/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16685698</a>] [<a href="https://doi.org/10.1002/ana.20869" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16685698">Martin-Ruiz et al. (2006)</a> found that longer telomeres in peripheral blood mononuclear cells (see <a href="/entry/609113">609113</a>) was associated with decreased risk for death (p = 0.04) and dementia (p = 0.002) and with a smaller reduction in Mini-Mental State Examination score (p = 0.04). The authors suggested that peripheral leukocyte telomere length may serve as a biomarker for long-term stroke outcomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16685698" 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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Ischemic stroke is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors, and can therefore be viewed as a paradigm for late-onset, complex polygenic diseases (see <a href="#12" class="mim-tip-reference" title="Dominiczak, A. F., McBride, M. W. <strong>Genetics of common polygenic stroke.</strong> Nature Genet. 35: 116-117, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14517535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14517535</a>] [<a href="https://doi.org/10.1038/ng1003-116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14517535">Dominiczak and McBride, 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14517535" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Several lines of evidence support a role for genetic factors in the pathogenesis of stroke. These include studies of twins (<a href="#5" class="mim-tip-reference" title="Brass, L. M., Isaacsohn, J. L., Merikangas, K. R., Robinette, C. D. <strong>A study of twins and stroke.</strong> Stroke 23: 221-223, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1561651/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1561651</a>] [<a href="https://doi.org/10.1161/01.str.23.2.221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1561651">Brass et al., 1992</a>) and familial aggregation (<a href="#6" class="mim-tip-reference" title="Brass, L. M., Shaker, L. A. <strong>Family history in patients with transient ischemic attacks.</strong> Stroke 22: 837-841, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1853402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1853402</a>] [<a href="https://doi.org/10.1161/01.str.22.7.837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1853402">Brass and Shaker, 1991</a>). Both environmental and genetic risk factors for ischemic stroke have been well characterized (<a href="#28" class="mim-tip-reference" title="Sacco, R. L., Benjamin, E. J., Broderick, J. P., Dyken, M., Easton, J. D., Feinberg, W. M., Goldstein, L. B., Gorelick, P. B., Howard, G., Kittner, S. J., Manolio, T. A., Whisnant, J. P., Wolf, P. A. <strong>Risk factors.</strong> Stroke 28: 1507-1517, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9227708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9227708</a>] [<a href="https://doi.org/10.1161/01.str.28.7.1507" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9227708">Sacco et al., 1997</a>). Chief among these are age (the single most important risk factor), hypertension, cardiac disease, sickle cell disease, and hyperhomocysteinemia. Intimal-medial thickness of the common and internal carotid arteries is strongly correlated with cerebrovascular accidents. <a href="#13" class="mim-tip-reference" title="Duggirala, R., Gonzalez Villalpando, C., O'Leary, D. H., Stern, M. P., Blangero, J. <strong>Genetic basis of variation in carotid artery wall thickness.</strong> Stroke 27: 833-837, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8623101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8623101</a>] [<a href="https://doi.org/10.1161/01.str.27.5.833" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8623101">Duggirala et al. (1996)</a> demonstrated high heritability, with 66 to 74.9% of the total variation being accounted for by genetic factors and the remainder being attributable to covariates such as lipids, diabetes, blood pressure, and smoking. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9227708+1561651+1853402+8623101" 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="#9" class="mim-tip-reference" title="Catto, A. J. <strong>Genetic aspects of the hemostatic system in cerebrovascular disease.</strong> Neurology 57 (suppl. 2): S24-S30, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11552051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11552051</a>] [<a href="https://doi.org/10.1212/wnl.57.suppl_2.s24" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11552051">Catto (2001)</a> reviewed evidence that stroke has a genetic basis and that the hemostatic system is an important risk factor for stroke. He evaluated the genetic regulation of a number of these hemostatic proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11552051" 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>Ischemic strokes can be further subdivided into large vessel strokes and those resulting from the occlusion of small intracerebral vessels. The majority of large vessel ischemic strokes are caused by thromboemboli arising from the carotid artery, aortic arch, or heart (<a href="#11" class="mim-tip-reference" title="Delanty, N., Vaughan, C. J. <strong>Vascular effects of statins in stroke.</strong> Stroke 28: 2315-2320, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9368582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9368582</a>] [<a href="https://doi.org/10.1161/01.str.28.11.2315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9368582">Delanty and Vaughan, 1997</a>). Small vessel strokes are associated with lipohyalinosis of small intracranial blood vessels observed as lacunae and leukoaraiosis on magnetic resonances imaging of the brain. Lacunar infarctions are associated with diabetes mellitus, hypertension, and disorders such as CADASIL (<a href="#26" class="mim-tip-reference" title="Pantoni, L., Garcia, J. H. <strong>Pathogenesis of leukoaraiosis: a review.</strong> Stroke 28: 652-659, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9056627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9056627</a>] [<a href="https://doi.org/10.1161/01.str.28.3.652" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9056627">Pantoni and Garcia, 1997</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9056627+9368582" 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>Hypertension</em></strong></p><p>
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The importance of hypertension in stroke pathogenesis has conclusively been shown by large randomized prospective trials, demonstrating that treatment of hypertension reduces the risk of stroke by at least 40% (<a href="#22" class="mim-tip-reference" title="MacMahon, S., Peto, R., Cutler, J., Collins, R., Sorlie, P., Neaton, J., Abbott, R., Godwin, J., Dyer, A., Stamler, J. <strong>Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias.</strong> Lancet 335: 765-774, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1969518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1969518</a>] [<a href="https://doi.org/10.1016/0140-6736(90)90878-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1969518">MacMahon et al., 1990</a>). Hypertension not only accelerates atherosclerosis in the large arteries but also affects smaller penetrating arteries of the brain by a process known as lipohyalinosis or fibrinoid necrosis. This process weakens the vessel wall, and extravasation of blood through the disintegrating wall follows. Ultimately, this results either in thrombosis or in rupture of the vessel wall. <a href="#15" class="mim-tip-reference" title="Gunel, M., Lifton, R. P. <strong>Counting strokes.</strong> Nature Genet. 13: 384-385, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8696326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8696326</a>] [<a href="https://doi.org/10.1038/ng0896-384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8696326">Gunel and Lifton (1996)</a> stated that not all hypertensive individuals develop lipohyalinosis, and lipohyalinosis has also been reported in normotensive individuals. These observations raise the possibility that genetic predisposition may be important in the pathogenesis of stroke. Such predisposition may include not only genes contributing to elevated blood pressure but also genes acting independently of blood pressure. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8696326+1969518" 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="#31" class="mim-tip-reference" title="Wang, Y., Meng, X., Wang, A., Xie, X., Pan, Y., Johnston, S. C., Li, H., Bath, P. M., Dong, Q., Xu, A., Jing, J., Lin, J., and 16 others. <strong>Ticagrelor versus clopidogrel in CYP2C19 loss-of-function carriers with stroke or TIA.</strong> New Eng. J. Med. 385: 2520-2530, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34708996/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34708996</a>] [<a href="https://doi.org/10.1056/NEJMoa2111749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34708996">Wang et al. (2021)</a> conducted a randomized, double-blind, placebo-controlled trial among 6,412 patients who had a previous minor ischemic stroke or transient ischemic attack (TIA) and who carried CYP2C19 (<a href="/entry/124020">124020</a>) loss-of-function alleles. Patients were randomized to receive either ticagrelor (3,205 patients) or clopidogrel (3,207 patients), along with aspirin, within 24 hours after symptom onset. Stroke occurred within 90 days in 6% of the ticagrelor group and in 7.6% of the clopidogrel group (hazard ratio, 0.77; 95% CI, 0.64-0.94; p = 0.008). The frequency of severe or moderate bleeding events did not differ between the 2 treatment groups; however, the risk for any bleeding event was higher among those taking ticagrelor (5.3%) than those taking clopidogrel (2.5%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34708996" 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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See ATFB5 (<a href="/entry/611494">611494</a>) for discussion of a possible association between SNPs at chromosome 4q25 and the cardioembolic subtype of ischemic stroke.</p><p>In a genomewide association study of 4 large cohorts including 19,602 Caucasians in whom 1,544 incident strokes (1,164 ischemic strokes) developed over an average follow-up of 11 years, <a href="#18" class="mim-tip-reference" title="Ikram, M. A., Seshadri, S., Bis, J. C., Fornage, M., DeStefano, A. L., Aulchenko, Y. S., Debette, S., Lumley, T., Folsom, A. R., van den Herik, E. G., Bos, M. J., Beiser, A., and 34 others. <strong>Genomewide association studies of stroke.</strong> New Eng. J. Med. 360: 1718-1728, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19369658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19369658</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19369658[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/10.1056/NEJMoa0900094" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19369658">Ikram et al. (2009)</a> found linkage to <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11833579;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs11833579</a> and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12425791;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12425791</a> on chromosome 12p13 near or within the NINJ2 gene (<a href="/entry/607297">607297</a>). Both SNPs showed significant associations with total stroke (p = 4.8 x 10(-9) and p = 1.5 x 10(-8), respectively) and ischemic stroke (p = 2.3 x 10(-10) and p = 2.6 x 10(-9), respectively). A significant association with <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12425791;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12425791</a> was replicated in 3 additional cohorts, yielding an overall hazard ratio of 1.29 (p = 1.1 x 10(-9)). However, the <a href="#19" class="mim-tip-reference" title="International Stroke Genetics Consortium, Wellcome Trust Case-Control Consortium 2. <strong>Failure to validate association between 12p13 variants and ischemic stroke. (Letter)</strong> New Eng. J. Med. 362: 1547-1550, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20410525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20410525</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20410525[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/10.1056/NEJMc0910050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20410525">International Stroke Genetics Consortium and Wellcome Trust Case-Control Consortium 2 (2010)</a> failed to replicate an association between ischemic stroke and the variants <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11833579;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs11833579</a> and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12425791;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12425791</a> on 12p13 in a combined sample of 8,637 cases and 8,733 controls of European ancestry, as well as in a population-based genomewide cohort study of 278 ischemic strokes among 22,054 participants. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20410525+19369658" 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="#25" class="mim-tip-reference" title="Matsushita, T., Umeno, J., Hirakawa, Y., Yonemoto, K., Ashikawa, K., Amitani, H., Ninomiya, T., Hata, J., Doi, Y., Kitazono, T., Iida, M., Nakamura, Y., Kiyohara, Y., Kubo, M. <strong>Association study of the polymorphisms on chromosome 12p13 with atherothrombotic stroke in the Japanese population.</strong> J. Hum. Genet. 55: 473-476, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20448654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20448654</a>] [<a href="https://doi.org/10.1038/jhg.2010.45" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20448654">Matsushita et al. (2010)</a> specifically examined the association of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11833579;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs11833579</a> and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12425791;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12425791</a> with ischemic stroke in a case-control study of 3,784 Japanese patients and 3,102 Japanese controls. After adjustment for age and cardiovascular risk factors, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12425791;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12425791</a> was significantly associated with atherothrombotic stroke (p = 0.0084; odds ratio of 1.15) in the total cohort. However, after sex stratification, the association was no longer significant for males (p = 0.086) and showed only a weak association with females (p = 0.027). There was no association between stroke and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11833579;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs11833579</a> in any of the comparisons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20448654" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Matsushita, T., Ashikawa,, K., Yonemoto, K., Hirakawa, Y., Hata, J., Amitani, H., Doi, Y., Ninomiya, T., Kitazono, T., Ibayashi, S., Iida, M., Nakamura, Y., Kiyohara, Y., Kubo, M. <strong>Functional SNP of ARHGEF10 confers risk of atherothrombotic stroke.</strong> Hum. Molec. Genet. 19: 1137-1146, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20042462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20042462</a>] [<a href="https://doi.org/10.1093/hmg/ddp582" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20042462">Matsushita et al. (2010)</a> performed a large case-control association study and a replication study in a total of 2,775 cases with atherothrombotic stroke and 2,839 controls. Through the analysis in 860 cases and 860 age- and sex-matched controls, the SNP <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2280887;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2280887</a> in ARHGEF10 (<a href="/entry/608136">608136</a>) was significantly associated with atherothrombotic stroke even after the adjustment of multiple testing by a permutation test. The association was replicated in an independent set of 1,915 cases and 1,979 controls. Subsequent fine mapping found another 3 SNPs that showed similar association due to strong linkage disequilibrium to <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2280887;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2280887</a>. In the functional analyses of these 4 highly associated SNPs, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs4376531;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs4376531</a> affected ARHGEF10 transcriptional activity due to a difference in SP1 (<a href="/entry/189906">189906</a>)-binding affinity. In a small GTPase activity assay, the gene product of ARHGEF10 specifically activated RHOA (<a href="/entry/165390">165390</a>). A population-based cohort study revealed that subjects with <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs4376531;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs4376531</a> CC or CG had an increased incidence of ischemic stroke (P = 0.033). The authors suggested that the functional SNP of ARHGEF10 confers susceptibility to atherothrombotic stroke. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20042462" 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="#10" class="mim-tip-reference" title="Chen, J., Yang, T., Yu, H., Sun, K., Shi, Y., Song, W., Bai, Y., Wang, X., Lou, K., Song, Y., Zhang, Y., Hui, R. <strong>A functional variant in the 3-prime-UTR of angiopoietin-1 might reduce stroke risk by interfering with the binding efficiency of microRNA 211.</strong> Hum. Molec. Genet. 19: 2524-2533, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20378606/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20378606</a>] [<a href="https://doi.org/10.1093/hmg/ddq131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20378606">Chen et al. (2010)</a> identified a single-nucleotide polymorphism (SNP), <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2507800;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2507800</a>, within the 3-prime untranslated region (UTR) of angiopoietin-1 (ANGPT1; <a href="/entry/601667">601667</a>) that influences regulation of angiopoietin-1 by miR211 (<a href="/entry/613753">613753</a>). The A allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2507800;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2507800</a>, but not the T allele, suppressed angiopoietin-1 translation by facilitating miR211 binding. Subjects carrying the TT genotype had higher plasma angiopoietin-1 levels than those with the A allele. The association of the variant with stroke was tested in 438 stroke patients and 890 controls, and replicated in an independent population of 1791 stroke patients and 1843 controls. The TT genotype resulted in a significant reduction in overall stroke risk (p = 0.0003), ischemic stroke (p = 0.007) and hemorrhagic stroke (p = 0.007). These results were confirmed in an independent study. The authors concluded that the TT genotype of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2507800;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2507800</a> in the 3-prime UTR of angiopoietin-1 might reduce the risk of stroke by interfering with miR211 binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20378606" 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="#33" class="mim-tip-reference" title="Zee, R. Y. L., Cook, N. R., Cheng, S., Reynolds, R., Erlich, H. A., Lindpaintner, K., Ridker, P. M. <strong>Polymorphism in the P-selectin and interleukin-4 genes as determinants of stroke: a population-based, prospective genetic analysis.</strong> Hum. Molec. Genet. 13: 389-396, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14681304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14681304</a>] [<a href="https://doi.org/10.1093/hmg/ddh039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14681304">Zee et al. (2004)</a> collected DNA samples at baseline in a prospective cohort of 14,916 initially healthy American men. The authors then genotyped 92 polymorphisms from 56 candidate genes among 319 individuals who subsequently developed ischemic stroke and among 2,092 individuals who remained free of reported cardiovascular disease over a mean follow-up period of 13.2 years. Two polymorphisms related to inflammation, val640-to-leu in the SELP gene (<a href="/entry/173610#0002">173610.0002</a>) and a 582C-T transition in the IL4 gene (<a href="/entry/147780">147780</a>), were found to be independent predictors of thromboembolic stroke (odds ratio of 1.63, P = 0.001, and odds ratio of 1.40, P = 0.003, respectively). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14681304" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Casas, J. P., Hingorani, A. D., Bautista, L. E., Sharma, P. <strong>Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18000 cases and 58000 controls.</strong> Arch. Neurol. 61: 1652-1662, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15534175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15534175</a>] [<a href="https://doi.org/10.1001/archneur.61.11.1652" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15534175">Casas et al. (2004)</a> performed a comprehensive metaanalysis of 120 case-control studies of genetic associations in ischemic stroke in white adults and determined the pooled odds ratios (OR) conferred by specific genetic changes. Statistically significant associations were identified for 4 polymorphisms: factor V Leiden (R506Q; <a href="/entry/612309#0001">612309.0001</a>, OR of 1.33); methylenetetrahydrofolate reductase (A222V; <a href="/entry/607093#0003">607093.0003</a>, OR of 1.24); prothrombin (20210G-A; <a href="/entry/176930#0009">176930.0009</a>, OR of 1.44); and angiotensin-converting enzyme (insertion/deletion, OR of 1.21). These were also the most investigated candidate genes, including 4,588, 3,387, 3,028, and 2,990 cases, respectively. No statistically significant association with ischemic stroke was detected for the 3 next most investigated genes: factor VIII (<a href="/entry/300841">300841</a>), apolipoprotein E (<a href="/entry/107741">107741</a>), and human platelet antigen type 1 (<a href="/entry/173470">173470</a>). <a href="#8" class="mim-tip-reference" title="Casas, J. P., Hingorani, A. D., Bautista, L. E., Sharma, P. <strong>Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18000 cases and 58000 controls.</strong> Arch. Neurol. 61: 1652-1662, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15534175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15534175</a>] [<a href="https://doi.org/10.1001/archneur.61.11.1652" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15534175">Casas et al. (2004)</a> concluded that although there is no single gene with a major effect, common variants in several genes contribute to the risk of stroke. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15534175" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a genomewide scan of 296 multiplex Icelandic families including 713 individuals with myocardial infarction (<a href="/entry/608557">608557</a>), <a href="#17" class="mim-tip-reference" title="Helgadottir, A., Manolescu, A., Thorleifsson, G., Gretarsdottir, S., Jonsdottir, H., Thorsteinsdottir, U., Samani, N. J., Gudmundsson, G., Grant, S. F. A., Thorgeirsson, G., Sveinbjornsdottir, S., Valdimarsson, E. M., and 14 others. <strong>The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke.</strong> Nature Genet. 36: 233-239, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14770184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14770184</a>] [<a href="https://doi.org/10.1038/ng1311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14770184">Helgadottir et al. (2004)</a> found suggestive linkage to chromosome 13q12-q13. By analysis of a candidate gene in the region, ALOX5AP (<a href="/entry/603700">603700</a>), they identified a 4-SNP haplotype, 'HapA' (defined by SG13S25, SG13S114, SG13S89, and SG13S32), that conferred a nearly 2 times greater risk of myocardial infarction and stroke. Another 4-SNP haplotype, 'HapB', was associated only with myocardial infarction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14770184" 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 further the contribution of the ALOX5AP variants HapA and HapB in a population outside Iceland, <a href="#16" class="mim-tip-reference" title="Helgadottir, A., Gretarsdottir, S., St. Clair, D., Manolescu, A., Cheung, J., Thorleifsson, G., Pasdar, A., Grant, S. F. A., Whalley, L. J., Hakonarson, H., Thorsteinsdottir, U., Kong, A., Gulcher, J., Stefansson, K., MacLeod, M. J. <strong>Association between the gene encoding 5-lipoxygenase-activating protein and stroke replicated in a Scottish population.</strong> Am. J. Hum. Genet. 76: 505-509, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15640973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15640973</a>] [<a href="https://doi.org/10.1086/428066" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15640973">Helgadottir et al. (2005)</a> genotyped 7 SNPs that defined both of these haplotypes from 450 patients with ischemic stroke and 710 controls from Aberdeenshire, Scotland. The haplotype that was at-risk in Iceland, HapA, had significantly greater frequency in Scottish patients than in controls. The carrier frequency in patients and controls was 33.4% and 26.4%, respectively, which resulted in a relative risk of 1.36 under the assumption of a multiplicative model (p = 0.007). They did not detect association between HapB and ischemic stroke in the Scottish cohort. However, HapB was overrepresented in male patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15640973" 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="#14" class="mim-tip-reference" title="Fornage, M., Lee, C. R., Doris, P. A., Bray, M. S., Heiss, G., Zeldin, D. C., Boerwinkle, E. <strong>The soluble epoxide hydrolase gene harbors sequence variation associated with susceptibility to and protection from incident ischemic stroke.</strong> Hum. Molec. Genet. 14: 2829-2837, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16115816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16115816</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16115816[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/10.1093/hmg/ddi315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16115816">Fornage et al. (2005)</a> genotyped 12 SNPs in the EPHX2 gene (<a href="/entry/132811">132811</a>) in 315 stroke patients and 1,021 controls from the ARIC study and identified 2 common EPHX2 haplotypes that were associated with increased and decreased risk of ischemic stroke in African Americans (adjusted p less than 0.04). In whites, 2 different common haplotypes showed suggestive evidence for association with ischemic stroke risk but, as in African Americans, these relationships were in opposite direction. <a href="#14" class="mim-tip-reference" title="Fornage, M., Lee, C. R., Doris, P. A., Bray, M. S., Heiss, G., Zeldin, D. C., Boerwinkle, E. <strong>The soluble epoxide hydrolase gene harbors sequence variation associated with susceptibility to and protection from incident ischemic stroke.</strong> Hum. Molec. Genet. 14: 2829-2837, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16115816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16115816</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16115816[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/10.1093/hmg/ddi315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16115816">Fornage et al. (2005)</a> suggested that multiple variants may exist within or near the EPHX2 gene, with greatly contrasting relationships to ischemic stroke incidence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16115816" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In large studies in Japan, <a href="#21" class="mim-tip-reference" title="Kubo, M., Hata, J., Ninomiya, T., Matsuda, K., Yonemoto, K., Nakano, T., Matsushita, T., Yamazaki, K., Ohnishi, Y., Saito, S., Kitazono, T., Ibayashi, S., Sueishi, K., Iida, M., Nakamura, Y., Kiyohara, Y. <strong>A nonsynonymous SNP in PRKCH (protein kinase C eta) increases the risk of cerebral infarction.</strong> Nature Genet. 39: 212-217, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17206144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17206144</a>] [<a href="https://doi.org/10.1038/ng1945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17206144">Kubo et al. (2007)</a> demonstrated association between cerebral infarction (ischemic stroke) and a nonsynonymous SNP in the PRKCH gene (V374I; <a href="/entry/605437#0001">605437.0001</a>), which caused enhancement of PKC activity in transfected 293T cells. Furthermore, <a href="#21" class="mim-tip-reference" title="Kubo, M., Hata, J., Ninomiya, T., Matsuda, K., Yonemoto, K., Nakano, T., Matsushita, T., Yamazaki, K., Ohnishi, Y., Saito, S., Kitazono, T., Ibayashi, S., Sueishi, K., Iida, M., Nakamura, Y., Kiyohara, Y. <strong>A nonsynonymous SNP in PRKCH (protein kinase C eta) increases the risk of cerebral infarction.</strong> Nature Genet. 39: 212-217, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17206144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17206144</a>] [<a href="https://doi.org/10.1038/ng1945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17206144">Kubo et al. (2007)</a> found that PKC-eta was expressed mainly in vascular endothelial cells and foamy macrophages in human atherosclerotic lesions, and its expression increased as the lesion type progressed. These results supported a role for PRKCH in the pathogenesis of cerebral infarction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17206144" 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="#3" class="mim-tip-reference" title="Berger, K., Stogbauer, F., Stoll, M., Wellmann, J., Huge, A., Cheng, S., Kessler, C., John, U., Assmann, G., Ringelstein, E. B., Funke, H. <strong>The glu298asp polymorphism in the nitric oxide synthase 3 gene is associated with the risk of ischemic stroke in two large independent case-control studies.</strong> Hum. Genet. 121: 169-178, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17165044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17165044</a>] [<a href="https://doi.org/10.1007/s00439-006-0302-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17165044">Berger et al. (2007)</a> performed 2 large case-control studies involving 1,901 hospitalized stroke patients and 1,747 regional population controls and found that the E298D polymorphism of the NOS3 gene (<a href="/entry/163729#0001">163729.0001</a>) was significantly associated with ischemic stroke independent of age, gender, hypertension, diabetes, and hypercholesterolemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17165044" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Zacho, J., Tybjaerg-Hansen, A., Jensen, J. S., Grande, P., Sillesen, H., Nordestgaard, B. G. <strong>Genetically elevated C-reactive protein and ischemic vascular disease.</strong> New Eng. J. Med. 359: 1897-1908, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18971492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18971492</a>] [<a href="https://doi.org/10.1056/NEJMoa0707402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18971492">Zacho et al. (2008)</a> studied 10,276 persons from a general population cohort, including 1,786 in whom ischemic heart disease developed (see <a href="/entry/607339">607339</a>) and 741 in whom ischemic cerebrovascular disease developed, and an additional 31,992 persons from a cross-sectional general population study, of whom 2,521 had ischemic heart disease and 1,483 had ischemic cerebrovascular disease. Finally, <a href="#32" class="mim-tip-reference" title="Zacho, J., Tybjaerg-Hansen, A., Jensen, J. S., Grande, P., Sillesen, H., Nordestgaard, B. G. <strong>Genetically elevated C-reactive protein and ischemic vascular disease.</strong> New Eng. J. Med. 359: 1897-1908, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18971492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18971492</a>] [<a href="https://doi.org/10.1056/NEJMoa0707402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18971492">Zacho et al. (2008)</a> compared 2,238 patients with ischemic heart disease with 4,474 control subjects and 612 patients with ischemic cerebrovascular disease with 1,224 control subjects. <a href="#32" class="mim-tip-reference" title="Zacho, J., Tybjaerg-Hansen, A., Jensen, J. S., Grande, P., Sillesen, H., Nordestgaard, B. G. <strong>Genetically elevated C-reactive protein and ischemic vascular disease.</strong> New Eng. J. Med. 359: 1897-1908, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18971492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18971492</a>] [<a href="https://doi.org/10.1056/NEJMoa0707402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18971492">Zacho et al. (2008)</a> measured levels of high-sensitivity C-reactive protein (CRP: <a href="/entry/123260">123260</a>) and conducted genotyping for 4 CRP polymorphisms and 2 apolipoprotein E polymorphisms (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs429358;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs429358</a> and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs7412;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs7412</a>). The risk of ischemic heart disease and ischemic cerebrovascular disease was increased by a factor of 1.6 and 1.3, respectively, in persons who had CRP levels above 3 mg per liter, as compared with persons who had CRP levels below 1 mg per liter. Genotype combinations of the 4 CRP polymorphisms <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1205;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1205</a>, {dbSNP 1130864}, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3091244;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3091244</a>, and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3093077;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3093077</a> were associated with an increase in CRP levels up to 64%, resulting in a theoretically predicted increased risk of up to 32% for ischemic heart disease and up to 25% for ischemic cerebrovascular disease. However, these genotype combinations were not associated with an increased risk of ischemic vascular disease. In contrast, <a href="#32" class="mim-tip-reference" title="Zacho, J., Tybjaerg-Hansen, A., Jensen, J. S., Grande, P., Sillesen, H., Nordestgaard, B. G. <strong>Genetically elevated C-reactive protein and ischemic vascular disease.</strong> New Eng. J. Med. 359: 1897-1908, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18971492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18971492</a>] [<a href="https://doi.org/10.1056/NEJMoa0707402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18971492">Zacho et al. (2008)</a> found that apolipoprotein E genotypes were associated with both elevated cholesterol levels and increased risk of ischemic heart disease. <a href="#32" class="mim-tip-reference" title="Zacho, J., Tybjaerg-Hansen, A., Jensen, J. S., Grande, P., Sillesen, H., Nordestgaard, B. G. <strong>Genetically elevated C-reactive protein and ischemic vascular disease.</strong> New Eng. J. Med. 359: 1897-1908, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18971492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18971492</a>] [<a href="https://doi.org/10.1056/NEJMoa0707402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18971492">Zacho et al. (2008)</a> concluded that polymorphisms in the CRP gene are associated with marked increases in CRP levels, but that these are not in themselves associated with an increased risk of ischemic vascular disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18971492" 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="#27" class="mim-tip-reference" title="Rubattu, S., Volpe, M., Kreutz, R., Ganten, U., Ganten, D., Lindpaintner, K. <strong>Chromosomal mapping of quantitative trait loci contributing to stroke in a rat model of complex human disease.</strong> Nature Genet. 13: 429-434, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8696337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8696337</a>] [<a href="https://doi.org/10.1038/ng0896-429" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8696337">Rubattu et al. (1996)</a> reported the chromosomal mapping of quantitative trait loci (QTLs) contributing to stroke in a rat model of this complex disorder of multifactorial and polygenic etiology. Using the stroke-prone spontaneously hypertensive rat (SHRSP) as a model organism, they mated it with the stroke-resistant spontaneously hypertensive rat (SHR) and performed a genomewide screen in the resultant F2 cohort where latency until stroke, but not hypertension (a major confounder), segregated. They identified 3 major QTLs: STR1, STR2, and STR3, with lod scores of 7.4, 4.7, and 3.0, respectively. These 3 QTLs accounted for 28% of the overall phenotypic variants. STR1 mapped to rat chromosome 1 and strongly affected latency to stroke in a recessive mode, accounting for 17.3% of overall phenotypic variants in the cross studied. Additional consideration of age-adjusted blood pressure values as a covariate had no effects on the resultant statistic, indicating to <a href="#27" class="mim-tip-reference" title="Rubattu, S., Volpe, M., Kreutz, R., Ganten, U., Ganten, D., Lindpaintner, K. <strong>Chromosomal mapping of quantitative trait loci contributing to stroke in a rat model of complex human disease.</strong> Nature Genet. 13: 429-434, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8696337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8696337</a>] [<a href="https://doi.org/10.1038/ng0896-429" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8696337">Rubattu et al. (1996)</a> that this locus acts independently of blood pressure. STR2, on the other hand, conferred a significant protective effect against stroke in the presence of SHRSP alleles. STR2 accounted for 9.6% of overall variants in stroke latency. The peak protective effect mapped close to the gene coding for atrial natriuretic factor (ANF; <a href="/entry/108780">108780</a>) on rat chromosome 5. In the rat, as in man and mouse, the gene for brain natriuretic factor, BNF, colocalizes with ANF. STR3, a locus linked to rat chromosome 4, conferred a similar, but less significant, recessive effect on preventing stroke in the presence of 2 SHRSP-derived alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8696337" 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>Building on the work of <a href="#27" class="mim-tip-reference" title="Rubattu, S., Volpe, M., Kreutz, R., Ganten, U., Ganten, D., Lindpaintner, K. <strong>Chromosomal mapping of quantitative trait loci contributing to stroke in a rat model of complex human disease.</strong> Nature Genet. 13: 429-434, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8696337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8696337</a>] [<a href="https://doi.org/10.1038/ng0896-429" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8696337">Rubattu et al. (1996)</a>, <a href="#20" class="mim-tip-reference" title="Jeffs, B., Clark, J. S., Anderson, N. H., Gratton, J., Brosnan, M. J., Gauguier, D., Reid, J. L., Macrae, I. M., Dominiczak, A. F. <strong>Sensitivity to cerebral ischaemic insult in a rat model of stroke is determined by a single genetic locus.</strong> Nature Genet. 16: 364-367, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9241273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9241273</a>] [<a href="https://doi.org/10.1038/ng0897-364" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9241273">Jeffs et al. (1997)</a> designed studies to identify the genetic component responsible for large infarct volumes in the SHRSP in response to a focal ischemic insult by performing a genome scan in a F2 cross derived from the SHRSP and the normotensive reference rat strain WKY. They identified a highly significant QTL on rat chromosome 5 with a lod score of 16.6 that accounted for 67% of the total variance, colocalized with the genes encoding the atrial and brain natriuretic factors (see <a href="/entry/108780">108780</a> and <a href="/entry/600295">600295</a>), and was blood pressure independent. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8696337+9241273" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a rat model of ischemic stroke, <a href="#29" class="mim-tip-reference" title="Simard, J. M., Chen, M., Tarasov, K. V., Bhatta, S., Ivanova, S., Melnitchenko, L., Tsymbalyuk, N., West, G. A., Gerzanich, V. <strong>Newly expressed SUR1-regulated NC(Ca-ATP) channel mediates cerebral edema after ischemic stroke.</strong> Nature Med. 12: 433-440, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16550187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16550187</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16550187[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm1390" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16550187">Simard et al. (2006)</a> found upregulation of the cation channel regulatory subunit Sur1 (<a href="/entry/600509">600509</a>) in ischemic neurons, astrocytes, and capillaries. Upregulation of Sur1 was linked to activation of the transcription factor Sp1 (<a href="/entry/189906">189906</a>) and was associated with expression of functional nonselective cation channels, which they called the NC(Ca-ATP) channel, but not K(ATP) channels. Treatment with low-dose glibenclamide, which blocks Sur1 and the NC(Ca-ATP) channel, reduced cerebral edema, infarct volume, and mortality by 50%. <a href="#29" class="mim-tip-reference" title="Simard, J. M., Chen, M., Tarasov, K. V., Bhatta, S., Ivanova, S., Melnitchenko, L., Tsymbalyuk, N., West, G. A., Gerzanich, V. <strong>Newly expressed SUR1-regulated NC(Ca-ATP) channel mediates cerebral edema after ischemic stroke.</strong> Nature Med. 12: 433-440, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16550187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16550187</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16550187[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm1390" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16550187">Simard et al. (2006)</a> concluded that the NC(Ca-ATP) channel is involved in the development of cerebral edema and that targeting Sur1 may provide a new therapeutic approach to stroke. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16550187" 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="#1" class="mim-tip-reference" title="Arboleda-Velasquez, J. F., Zhou, Z., Shin, H. K., Louvi, A., Kim, H.-H., Savitz, S. I., Liao, J. K., Salomone, S., Ayata, C., Moskowitz, M. A., Artavanis-Tsakonas, S. <strong>Linking Notch signaling to ischemic stroke.</strong> Proc. Nat. Acad. Sci. 105: 4856-4861, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18347334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18347334</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18347334[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0709867105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18347334">Arboleda-Velasquez et al. (2008)</a> found that Notch3 knockout increased susceptibility of mice to ischemic challenge. Notch3-null mice showed larger ischemic lesions, more neurologic deficits, increased mortality, more severe cerebral blood flow deficits, and more frequent spontaneous periinfarct depolarizations compared with wildtype mice. Microarray analysis revealed over 600 differentially regulated genes, and all genes that regulate muscle contraction were downregulated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18347334" 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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Arboleda-Velasquez, J. F., Zhou, Z., Shin, H. K., Louvi, A., Kim, H.-H., Savitz, S. I., Liao, J. K., Salomone, S., Ayata, C., Moskowitz, M. A., Artavanis-Tsakonas, S.
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[<a href="https://doi.org/10.1073/pnas.0709867105" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000168862.09764.9f" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-006-0302-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.20666" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/01.str.23.2.221" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/01.str.22.7.837" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.61.11.1652" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<span class="mim-text-font">
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Sonja A. Rasmussen - updated : 07/25/2022
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George E. Tiller - updated : 08/08/2013<br>George E. Tiller - updated : 11/10/2011<br>Cassandra L. Kniffin - updated : 8/18/2010<br>Cassandra L. Kniffin - updated : 4/22/2010<br>George E. Tiller - updated : 4/22/2009<br>Marla J. F. O'Neill - updated : 3/3/2009<br>Ada Hamosh - updated : 11/24/2008<br>Marla J. F. O'Neill - updated : 10/16/2008<br>Patricia A. Hartz - updated : 9/4/2008<br>Cassandra L. Kniffin - updated : 6/26/2008<br>Marla J. F. O'Neill - updated : 8/27/2007<br>Cassandra L. Kniffin - updated : 7/30/2007<br>Victor A. McKusick - updated : 2/23/2007<br>George E. Tiller - updated : 12/4/2006<br>Cassandra L. Kniffin - updated : 7/14/2006<br>Cassandra L. Kniffin - updated : 5/15/2006<br>Cassandra L. Kniffin - updated : 10/31/2005<br>Cassandra L. Kniffin - reorganized : 6/13/2005<br>Cassandra L. Kniffin - updated : 6/10/2005<br>Cassandra L. Kniffin - updated : 4/12/2005<br>Victor A. McKusick - updated : 10/1/2003<br>Victor A. McKusick - updated : 12/13/2002<br>Victor A. McKusick - updated : 3/21/2002<br>Victor A. McKusick - updated : 11/9/2001<br>Orest Hurko - updated : 4/6/1998<br>Victor A. McKusick - updated : 8/1/1997
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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Creation Date:
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<span class="mim-text-font">
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Victor A. McKusick : 8/9/1996
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carol : 07/26/2022
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carol : 07/25/2022<br>joanna : 04/28/2022<br>carol : 04/27/2022<br>alopez : 04/26/2022<br>joanna : 08/04/2016<br>alopez : 08/08/2013<br>carol : 3/7/2012<br>ckniffin : 3/5/2012<br>alopez : 11/21/2011<br>terry : 11/10/2011<br>carol : 4/7/2011<br>terry : 3/22/2011<br>carol : 3/10/2011<br>wwang : 8/24/2010<br>ckniffin : 8/18/2010<br>ckniffin : 8/18/2010<br>ckniffin : 8/18/2010<br>alopez : 4/23/2010<br>ckniffin : 4/22/2010<br>wwang : 7/30/2009<br>ckniffin : 7/14/2009<br>wwang : 5/8/2009<br>terry : 4/22/2009<br>terry : 3/3/2009<br>alopez : 12/15/2008<br>terry : 11/24/2008<br>carol : 10/17/2008<br>carol : 10/16/2008<br>carol : 10/9/2008<br>carol : 10/8/2008<br>wwang : 9/4/2008<br>wwang : 7/2/2008<br>ckniffin : 6/26/2008<br>wwang : 8/27/2007<br>wwang : 8/22/2007<br>ckniffin : 7/30/2007<br>alopez : 3/8/2007<br>terry : 2/23/2007<br>wwang : 12/4/2006<br>terry : 12/4/2006<br>carol : 7/19/2006<br>ckniffin : 7/14/2006<br>wwang : 5/24/2006<br>ckniffin : 5/15/2006<br>wwang : 11/3/2005<br>ckniffin : 10/31/2005<br>carol : 6/13/2005<br>carol : 6/13/2005<br>ckniffin : 6/10/2005<br>ckniffin : 6/10/2005<br>ckniffin : 6/10/2005<br>wwang : 4/25/2005<br>wwang : 4/14/2005<br>ckniffin : 4/12/2005<br>alopez : 10/7/2003<br>terry : 10/1/2003<br>tkritzer : 12/16/2002<br>terry : 12/13/2002<br>alopez : 3/27/2002<br>terry : 3/21/2002<br>terry : 3/21/2002<br>carol : 11/12/2001<br>terry : 11/9/2001<br>dkim : 12/10/1998<br>carol : 6/22/1998<br>terry : 6/1/1998<br>terry : 4/6/1998<br>terry : 8/5/1997<br>terry : 8/1/1997<br>mark : 7/8/1997<br>terry : 11/25/1996<br>jamie : 10/23/1996<br>jamie : 10/18/1996<br>jamie : 10/16/1996<br>mark : 8/30/1996<br>terry : 8/9/1996<br>mark : 8/9/1996
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<h3>
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<span class="mim-font">
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<strong>#</strong> 601367
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</h3>
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<div>
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<h3>
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STROKE, ISCHEMIC
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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CEREBROVASCULAR ACCIDENT<br />
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CEREBRAL INFARCTION
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 230690007, 422504002, 432504007;
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<strong>ICD10CM:</strong> I63, I63.9;
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<strong>DO:</strong> 3526;
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</p>
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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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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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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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<span class="mim-font">
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1q24.2
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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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{Stroke, ischemic, susceptibility to}
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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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601367
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</span>
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<td>
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<span class="mim-font">
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Multifactorial
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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F5
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<span class="mim-font">
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612309
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</span>
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</td>
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<span class="mim-font">
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7q36.1
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<td>
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<span class="mim-font">
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{Ischemic stroke, susceptibility to}
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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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601367
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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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Multifactorial
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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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3
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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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NOS3
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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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163729
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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11p11.2
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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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{Stroke, ischemic, susceptibility to}
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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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601367
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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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Multifactorial
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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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3
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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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F2
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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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176930
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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13q12.3
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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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{Stroke, susceptibility to}
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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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601367
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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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Multifactorial
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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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3
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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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ALOX5AP
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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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603700
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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14q23.1
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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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{Cerebral infarction, susceptibility to}
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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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601367
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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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Multifactorial
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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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3
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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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PRKCH
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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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605437
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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>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because common variants in several genes have been associated with increased susceptibility to development of ischemic stroke (see MOLECULAR GENETICS).</p><p>A locus for susceptibility to ischemic stroke has been mapped to chromosome 5q12 (STRK1; 606799).</p><p>Several conditions in which stroke occurs are inherited in a classic mendelian pattern. As reviewed by Tournier-Lasserve (2002), these monogenic disorders have a low prevalence but a high risk for stroke in mutation carriers. The genes that have been identified include APP (104760), BRI (603904), and CST3 (604312), causing autosomal dominant amyloid angiopathies; NOTCH3 (600276), causing cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; 125310); and KRIT1 (604214), causing cavernous angioma (116860). </p>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. It is said to be the third leading cause of death in the United States. Gunel and Lifton (1996) noted that about 20% of strokes are hemorrhagic, resulting in bleeding into the brain. Ischemic strokes, resulting from vascular occlusion, account for the majority of strokes. </p><p>Bersano et al. (2008) reviewed genetic polymorphisms that have been implicated in the development of stroke. Candidate genes include those involved in hemostasis (see, e.g., F5; 612309), the renin-angiotensin-aldosterone system (see, e.g., ACE; 106180), homocysteine (see, e.g., MTHFR; 607093), and lipoprotein metabolism (see, e.g., APOE; 107741). </p><p>See also hemorrhagic stroke, or intracerebral hemorrhage (ICH; 614519).</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Other Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Among 512 Korean patients with ischemic stroke, Bang et al. (2005) found a significant association between intracranial atherosclerotic stroke (143 patients) and components of the metabolic syndrome (AOMS1; 605552), compared to those with extracranial atherosclerotic stroke (77 patients) and those with nonatherosclerotic stroke (292 patients). The association was particularly strong with regard to hypertension, abdominal obesity, and HDL cholesterol levels. </p><p>Campbell et al. (2006) found that increased serum levels of soluble vascular adhesion molecule-1 (VCAM1; 192225) predicted recurrent ischemic stroke in a study of 252 patients. A smaller but similar trend was noted for serum levels of N-terminal pro-B-type natriuretic peptide (NPPB; 600295). Patients in the highest quarters for both sVCAM1 and NT-proBNP levels had 3.6 times the risk of recurrent ischemic stroke compared to patients in the lowest quarters for both biologic markers. </p><p>Among 195 nondemented stroke survivors over age 75 years who were followed for 2 years for cognitive decline and 5 years for survival, Martin-Ruiz et al. (2006) found that longer telomeres in peripheral blood mononuclear cells (see 609113) was associated with decreased risk for death (p = 0.04) and dementia (p = 0.002) and with a smaller reduction in Mini-Mental State Examination score (p = 0.04). The authors suggested that peripheral leukocyte telomere length may serve as a biomarker for long-term stroke outcomes. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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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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</div>
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<span class="mim-text-font">
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<p><strong><em>Genetic Factors</em></strong></p><p>
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Ischemic stroke is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors, and can therefore be viewed as a paradigm for late-onset, complex polygenic diseases (see Dominiczak and McBride, 2003). </p><p>Several lines of evidence support a role for genetic factors in the pathogenesis of stroke. These include studies of twins (Brass et al., 1992) and familial aggregation (Brass and Shaker, 1991). Both environmental and genetic risk factors for ischemic stroke have been well characterized (Sacco et al., 1997). Chief among these are age (the single most important risk factor), hypertension, cardiac disease, sickle cell disease, and hyperhomocysteinemia. Intimal-medial thickness of the common and internal carotid arteries is strongly correlated with cerebrovascular accidents. Duggirala et al. (1996) demonstrated high heritability, with 66 to 74.9% of the total variation being accounted for by genetic factors and the remainder being attributable to covariates such as lipids, diabetes, blood pressure, and smoking. </p><p>Catto (2001) reviewed evidence that stroke has a genetic basis and that the hemostatic system is an important risk factor for stroke. He evaluated the genetic regulation of a number of these hemostatic proteins. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Pathogenesis</strong>
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</span>
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</h4>
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<p>Ischemic strokes can be further subdivided into large vessel strokes and those resulting from the occlusion of small intracerebral vessels. The majority of large vessel ischemic strokes are caused by thromboemboli arising from the carotid artery, aortic arch, or heart (Delanty and Vaughan, 1997). Small vessel strokes are associated with lipohyalinosis of small intracranial blood vessels observed as lacunae and leukoaraiosis on magnetic resonances imaging of the brain. Lacunar infarctions are associated with diabetes mellitus, hypertension, and disorders such as CADASIL (Pantoni and Garcia, 1997). </p><p><strong><em>Hypertension</em></strong></p><p>
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The importance of hypertension in stroke pathogenesis has conclusively been shown by large randomized prospective trials, demonstrating that treatment of hypertension reduces the risk of stroke by at least 40% (MacMahon et al., 1990). Hypertension not only accelerates atherosclerosis in the large arteries but also affects smaller penetrating arteries of the brain by a process known as lipohyalinosis or fibrinoid necrosis. This process weakens the vessel wall, and extravasation of blood through the disintegrating wall follows. Ultimately, this results either in thrombosis or in rupture of the vessel wall. Gunel and Lifton (1996) stated that not all hypertensive individuals develop lipohyalinosis, and lipohyalinosis has also been reported in normotensive individuals. These observations raise the possibility that genetic predisposition may be important in the pathogenesis of stroke. Such predisposition may include not only genes contributing to elevated blood pressure but also genes acting independently of blood pressure. </p>
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<h4>
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<span class="mim-font">
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<strong>Clinical Management</strong>
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</h4>
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<p>Wang et al. (2021) conducted a randomized, double-blind, placebo-controlled trial among 6,412 patients who had a previous minor ischemic stroke or transient ischemic attack (TIA) and who carried CYP2C19 (124020) loss-of-function alleles. Patients were randomized to receive either ticagrelor (3,205 patients) or clopidogrel (3,207 patients), along with aspirin, within 24 hours after symptom onset. Stroke occurred within 90 days in 6% of the ticagrelor group and in 7.6% of the clopidogrel group (hazard ratio, 0.77; 95% CI, 0.64-0.94; p = 0.008). The frequency of severe or moderate bleeding events did not differ between the 2 treatment groups; however, the risk for any bleeding event was higher among those taking ticagrelor (5.3%) than those taking clopidogrel (2.5%). </p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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<p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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See ATFB5 (611494) for discussion of a possible association between SNPs at chromosome 4q25 and the cardioembolic subtype of ischemic stroke.</p><p>In a genomewide association study of 4 large cohorts including 19,602 Caucasians in whom 1,544 incident strokes (1,164 ischemic strokes) developed over an average follow-up of 11 years, Ikram et al. (2009) found linkage to rs11833579 and rs12425791 on chromosome 12p13 near or within the NINJ2 gene (607297). Both SNPs showed significant associations with total stroke (p = 4.8 x 10(-9) and p = 1.5 x 10(-8), respectively) and ischemic stroke (p = 2.3 x 10(-10) and p = 2.6 x 10(-9), respectively). A significant association with rs12425791 was replicated in 3 additional cohorts, yielding an overall hazard ratio of 1.29 (p = 1.1 x 10(-9)). However, the International Stroke Genetics Consortium and Wellcome Trust Case-Control Consortium 2 (2010) failed to replicate an association between ischemic stroke and the variants rs11833579 and rs12425791 on 12p13 in a combined sample of 8,637 cases and 8,733 controls of European ancestry, as well as in a population-based genomewide cohort study of 278 ischemic strokes among 22,054 participants. </p><p>Matsushita et al. (2010) specifically examined the association of rs11833579 and rs12425791 with ischemic stroke in a case-control study of 3,784 Japanese patients and 3,102 Japanese controls. After adjustment for age and cardiovascular risk factors, rs12425791 was significantly associated with atherothrombotic stroke (p = 0.0084; odds ratio of 1.15) in the total cohort. However, after sex stratification, the association was no longer significant for males (p = 0.086) and showed only a weak association with females (p = 0.027). There was no association between stroke and rs11833579 in any of the comparisons. </p><p>Matsushita et al. (2010) performed a large case-control association study and a replication study in a total of 2,775 cases with atherothrombotic stroke and 2,839 controls. Through the analysis in 860 cases and 860 age- and sex-matched controls, the SNP rs2280887 in ARHGEF10 (608136) was significantly associated with atherothrombotic stroke even after the adjustment of multiple testing by a permutation test. The association was replicated in an independent set of 1,915 cases and 1,979 controls. Subsequent fine mapping found another 3 SNPs that showed similar association due to strong linkage disequilibrium to rs2280887. In the functional analyses of these 4 highly associated SNPs, rs4376531 affected ARHGEF10 transcriptional activity due to a difference in SP1 (189906)-binding affinity. In a small GTPase activity assay, the gene product of ARHGEF10 specifically activated RHOA (165390). A population-based cohort study revealed that subjects with rs4376531 CC or CG had an increased incidence of ischemic stroke (P = 0.033). The authors suggested that the functional SNP of ARHGEF10 confers susceptibility to atherothrombotic stroke. </p><p>Chen et al. (2010) identified a single-nucleotide polymorphism (SNP), rs2507800, within the 3-prime untranslated region (UTR) of angiopoietin-1 (ANGPT1; 601667) that influences regulation of angiopoietin-1 by miR211 (613753). The A allele of rs2507800, but not the T allele, suppressed angiopoietin-1 translation by facilitating miR211 binding. Subjects carrying the TT genotype had higher plasma angiopoietin-1 levels than those with the A allele. The association of the variant with stroke was tested in 438 stroke patients and 890 controls, and replicated in an independent population of 1791 stroke patients and 1843 controls. The TT genotype resulted in a significant reduction in overall stroke risk (p = 0.0003), ischemic stroke (p = 0.007) and hemorrhagic stroke (p = 0.007). These results were confirmed in an independent study. The authors concluded that the TT genotype of rs2507800 in the 3-prime UTR of angiopoietin-1 might reduce the risk of stroke by interfering with miR211 binding. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Zee et al. (2004) collected DNA samples at baseline in a prospective cohort of 14,916 initially healthy American men. The authors then genotyped 92 polymorphisms from 56 candidate genes among 319 individuals who subsequently developed ischemic stroke and among 2,092 individuals who remained free of reported cardiovascular disease over a mean follow-up period of 13.2 years. Two polymorphisms related to inflammation, val640-to-leu in the SELP gene (173610.0002) and a 582C-T transition in the IL4 gene (147780), were found to be independent predictors of thromboembolic stroke (odds ratio of 1.63, P = 0.001, and odds ratio of 1.40, P = 0.003, respectively). </p><p>Casas et al. (2004) performed a comprehensive metaanalysis of 120 case-control studies of genetic associations in ischemic stroke in white adults and determined the pooled odds ratios (OR) conferred by specific genetic changes. Statistically significant associations were identified for 4 polymorphisms: factor V Leiden (R506Q; 612309.0001, OR of 1.33); methylenetetrahydrofolate reductase (A222V; 607093.0003, OR of 1.24); prothrombin (20210G-A; 176930.0009, OR of 1.44); and angiotensin-converting enzyme (insertion/deletion, OR of 1.21). These were also the most investigated candidate genes, including 4,588, 3,387, 3,028, and 2,990 cases, respectively. No statistically significant association with ischemic stroke was detected for the 3 next most investigated genes: factor VIII (300841), apolipoprotein E (107741), and human platelet antigen type 1 (173470). Casas et al. (2004) concluded that although there is no single gene with a major effect, common variants in several genes contribute to the risk of stroke. </p><p>In a genomewide scan of 296 multiplex Icelandic families including 713 individuals with myocardial infarction (608557), Helgadottir et al. (2004) found suggestive linkage to chromosome 13q12-q13. By analysis of a candidate gene in the region, ALOX5AP (603700), they identified a 4-SNP haplotype, 'HapA' (defined by SG13S25, SG13S114, SG13S89, and SG13S32), that conferred a nearly 2 times greater risk of myocardial infarction and stroke. Another 4-SNP haplotype, 'HapB', was associated only with myocardial infarction. </p><p>To assess further the contribution of the ALOX5AP variants HapA and HapB in a population outside Iceland, Helgadottir et al. (2005) genotyped 7 SNPs that defined both of these haplotypes from 450 patients with ischemic stroke and 710 controls from Aberdeenshire, Scotland. The haplotype that was at-risk in Iceland, HapA, had significantly greater frequency in Scottish patients than in controls. The carrier frequency in patients and controls was 33.4% and 26.4%, respectively, which resulted in a relative risk of 1.36 under the assumption of a multiplicative model (p = 0.007). They did not detect association between HapB and ischemic stroke in the Scottish cohort. However, HapB was overrepresented in male patients. </p><p>Fornage et al. (2005) genotyped 12 SNPs in the EPHX2 gene (132811) in 315 stroke patients and 1,021 controls from the ARIC study and identified 2 common EPHX2 haplotypes that were associated with increased and decreased risk of ischemic stroke in African Americans (adjusted p less than 0.04). In whites, 2 different common haplotypes showed suggestive evidence for association with ischemic stroke risk but, as in African Americans, these relationships were in opposite direction. Fornage et al. (2005) suggested that multiple variants may exist within or near the EPHX2 gene, with greatly contrasting relationships to ischemic stroke incidence. </p><p>In large studies in Japan, Kubo et al. (2007) demonstrated association between cerebral infarction (ischemic stroke) and a nonsynonymous SNP in the PRKCH gene (V374I; 605437.0001), which caused enhancement of PKC activity in transfected 293T cells. Furthermore, Kubo et al. (2007) found that PKC-eta was expressed mainly in vascular endothelial cells and foamy macrophages in human atherosclerotic lesions, and its expression increased as the lesion type progressed. These results supported a role for PRKCH in the pathogenesis of cerebral infarction. </p><p>Berger et al. (2007) performed 2 large case-control studies involving 1,901 hospitalized stroke patients and 1,747 regional population controls and found that the E298D polymorphism of the NOS3 gene (163729.0001) was significantly associated with ischemic stroke independent of age, gender, hypertension, diabetes, and hypercholesterolemia. </p><p>Zacho et al. (2008) studied 10,276 persons from a general population cohort, including 1,786 in whom ischemic heart disease developed (see 607339) and 741 in whom ischemic cerebrovascular disease developed, and an additional 31,992 persons from a cross-sectional general population study, of whom 2,521 had ischemic heart disease and 1,483 had ischemic cerebrovascular disease. Finally, Zacho et al. (2008) compared 2,238 patients with ischemic heart disease with 4,474 control subjects and 612 patients with ischemic cerebrovascular disease with 1,224 control subjects. Zacho et al. (2008) measured levels of high-sensitivity C-reactive protein (CRP: 123260) and conducted genotyping for 4 CRP polymorphisms and 2 apolipoprotein E polymorphisms (rs429358 and rs7412). The risk of ischemic heart disease and ischemic cerebrovascular disease was increased by a factor of 1.6 and 1.3, respectively, in persons who had CRP levels above 3 mg per liter, as compared with persons who had CRP levels below 1 mg per liter. Genotype combinations of the 4 CRP polymorphisms rs1205, {dbSNP 1130864}, rs3091244, and rs3093077 were associated with an increase in CRP levels up to 64%, resulting in a theoretically predicted increased risk of up to 32% for ischemic heart disease and up to 25% for ischemic cerebrovascular disease. However, these genotype combinations were not associated with an increased risk of ischemic vascular disease. In contrast, Zacho et al. (2008) found that apolipoprotein E genotypes were associated with both elevated cholesterol levels and increased risk of ischemic heart disease. Zacho et al. (2008) concluded that polymorphisms in the CRP gene are associated with marked increases in CRP levels, but that these are not in themselves associated with an increased risk of ischemic vascular disease. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Rubattu et al. (1996) reported the chromosomal mapping of quantitative trait loci (QTLs) contributing to stroke in a rat model of this complex disorder of multifactorial and polygenic etiology. Using the stroke-prone spontaneously hypertensive rat (SHRSP) as a model organism, they mated it with the stroke-resistant spontaneously hypertensive rat (SHR) and performed a genomewide screen in the resultant F2 cohort where latency until stroke, but not hypertension (a major confounder), segregated. They identified 3 major QTLs: STR1, STR2, and STR3, with lod scores of 7.4, 4.7, and 3.0, respectively. These 3 QTLs accounted for 28% of the overall phenotypic variants. STR1 mapped to rat chromosome 1 and strongly affected latency to stroke in a recessive mode, accounting for 17.3% of overall phenotypic variants in the cross studied. Additional consideration of age-adjusted blood pressure values as a covariate had no effects on the resultant statistic, indicating to Rubattu et al. (1996) that this locus acts independently of blood pressure. STR2, on the other hand, conferred a significant protective effect against stroke in the presence of SHRSP alleles. STR2 accounted for 9.6% of overall variants in stroke latency. The peak protective effect mapped close to the gene coding for atrial natriuretic factor (ANF; 108780) on rat chromosome 5. In the rat, as in man and mouse, the gene for brain natriuretic factor, BNF, colocalizes with ANF. STR3, a locus linked to rat chromosome 4, conferred a similar, but less significant, recessive effect on preventing stroke in the presence of 2 SHRSP-derived alleles. </p><p>Building on the work of Rubattu et al. (1996), Jeffs et al. (1997) designed studies to identify the genetic component responsible for large infarct volumes in the SHRSP in response to a focal ischemic insult by performing a genome scan in a F2 cross derived from the SHRSP and the normotensive reference rat strain WKY. They identified a highly significant QTL on rat chromosome 5 with a lod score of 16.6 that accounted for 67% of the total variance, colocalized with the genes encoding the atrial and brain natriuretic factors (see 108780 and 600295), and was blood pressure independent. </p><p>In a rat model of ischemic stroke, Simard et al. (2006) found upregulation of the cation channel regulatory subunit Sur1 (600509) in ischemic neurons, astrocytes, and capillaries. Upregulation of Sur1 was linked to activation of the transcription factor Sp1 (189906) and was associated with expression of functional nonselective cation channels, which they called the NC(Ca-ATP) channel, but not K(ATP) channels. Treatment with low-dose glibenclamide, which blocks Sur1 and the NC(Ca-ATP) channel, reduced cerebral edema, infarct volume, and mortality by 50%. Simard et al. (2006) concluded that the NC(Ca-ATP) channel is involved in the development of cerebral edema and that targeting Sur1 may provide a new therapeutic approach to stroke. </p><p>Arboleda-Velasquez et al. (2008) found that Notch3 knockout increased susceptibility of mice to ischemic challenge. Notch3-null mice showed larger ischemic lesions, more neurologic deficits, increased mortality, more severe cerebral blood flow deficits, and more frequent spontaneous periinfarct depolarizations compared with wildtype mice. Microarray analysis revealed over 600 differentially regulated genes, and all genes that regulate muscle contraction were downregulated. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<ol>
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Arboleda-Velasquez, J. F., Zhou, Z., Shin, H. K., Louvi, A., Kim, H.-H., Savitz, S. I., Liao, J. K., Salomone, S., Ayata, C., Moskowitz, M. A., Artavanis-Tsakonas, S.
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<strong>Linking Notch signaling to ischemic stroke.</strong>
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Proc. Nat. Acad. Sci. 105: 4856-4861, 2008.
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Bang, O. Y., Kim, J. W., Lee, J. H., Lee, M. A., Lee, P. H., Joo, I. S., Huh, K.
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Berger, K., Stogbauer, F., Stoll, M., Wellmann, J., Huge, A., Cheng, S., Kessler, C., John, U., Assmann, G., Ringelstein, E. B., Funke, H.
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<strong>The glu298asp polymorphism in the nitric oxide synthase 3 gene is associated with the risk of ischemic stroke in two large independent case-control studies.</strong>
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Hum. Genet. 121: 169-178, 2007.
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Bersano, A., Ballabio, E., Bresolin, N., Candelise, L.
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Brass, L. M., Isaacsohn, J. L., Merikangas, K. R., Robinette, C. D.
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<strong>A study of twins and stroke.</strong>
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Stroke 23: 221-223, 1992.
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Brass, L. M., Shaker, L. A.
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<strong>Family history in patients with transient ischemic attacks.</strong>
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Stroke 22: 837-841, 1991.
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[PubMed: 1853402]
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[Full Text: https://doi.org/10.1161/01.str.22.7.837]
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<p class="mim-text-font">
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Campbell, D. J., Woodward, M., Chalmers, J. P., Colman, S. A., Jenkins, A. J., Kemp, B. E., Neal, B. C., Patel, A., MacMahon, S. W.
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<strong>Soluble vascular cell adhesion molecule 1 and N-terminal pro-B-type natriuretic peptide in predicting ischemic stroke in patients with cerebrovascular disease.</strong>
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Arch. Neurol. 63: 60-65, 2006.
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[PubMed: 16286536]
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[Full Text: https://doi.org/10.1001/archneur.63.1.noc50221]
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Casas, J. P., Hingorani, A. D., Bautista, L. E., Sharma, P.
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<strong>Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18000 cases and 58000 controls.</strong>
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Arch. Neurol. 61: 1652-1662, 2004.
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[PubMed: 15534175]
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[Full Text: https://doi.org/10.1001/archneur.61.11.1652]
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<p class="mim-text-font">
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Catto, A. J.
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<strong>Genetic aspects of the hemostatic system in cerebrovascular disease.</strong>
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Neurology 57 (suppl. 2): S24-S30, 2001.
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[PubMed: 11552051]
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[Full Text: https://doi.org/10.1212/wnl.57.suppl_2.s24]
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<p class="mim-text-font">
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Chen, J., Yang, T., Yu, H., Sun, K., Shi, Y., Song, W., Bai, Y., Wang, X., Lou, K., Song, Y., Zhang, Y., Hui, R.
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<strong>A functional variant in the 3-prime-UTR of angiopoietin-1 might reduce stroke risk by interfering with the binding efficiency of microRNA 211.</strong>
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Hum. Molec. Genet. 19: 2524-2533, 2010.
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[PubMed: 20378606]
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[Full Text: https://doi.org/10.1093/hmg/ddq131]
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Delanty, N., Vaughan, C. J.
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<strong>Vascular effects of statins in stroke.</strong>
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Stroke 28: 2315-2320, 1997.
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[PubMed: 9368582]
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[Full Text: https://doi.org/10.1161/01.str.28.11.2315]
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Dominiczak, A. F., McBride, M. W.
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<strong>Genetics of common polygenic stroke.</strong>
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Nature Genet. 35: 116-117, 2003.
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[PubMed: 14517535]
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[Full Text: https://doi.org/10.1038/ng1003-116]
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<p class="mim-text-font">
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Duggirala, R., Gonzalez Villalpando, C., O'Leary, D. H., Stern, M. P., Blangero, J.
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<strong>Genetic basis of variation in carotid artery wall thickness.</strong>
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Stroke 27: 833-837, 1996.
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[PubMed: 8623101]
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[Full Text: https://doi.org/10.1161/01.str.27.5.833]
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Fornage, M., Lee, C. R., Doris, P. A., Bray, M. S., Heiss, G., Zeldin, D. C., Boerwinkle, E.
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<strong>The soluble epoxide hydrolase gene harbors sequence variation associated with susceptibility to and protection from incident ischemic stroke.</strong>
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Hum. Molec. Genet. 14: 2829-2837, 2005.
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Sonja A. Rasmussen - updated : 07/25/2022<br>George E. Tiller - updated : 08/08/2013<br>George E. Tiller - updated : 11/10/2011<br>Cassandra L. Kniffin - updated : 8/18/2010<br>Cassandra L. Kniffin - updated : 4/22/2010<br>George E. Tiller - updated : 4/22/2009<br>Marla J. F. O'Neill - updated : 3/3/2009<br>Ada Hamosh - updated : 11/24/2008<br>Marla J. F. O'Neill - updated : 10/16/2008<br>Patricia A. Hartz - updated : 9/4/2008<br>Cassandra L. Kniffin - updated : 6/26/2008<br>Marla J. F. O'Neill - updated : 8/27/2007<br>Cassandra L. Kniffin - updated : 7/30/2007<br>Victor A. McKusick - updated : 2/23/2007<br>George E. Tiller - updated : 12/4/2006<br>Cassandra L. Kniffin - updated : 7/14/2006<br>Cassandra L. Kniffin - updated : 5/15/2006<br>Cassandra L. Kniffin - updated : 10/31/2005<br>Cassandra L. Kniffin - reorganized : 6/13/2005<br>Cassandra L. Kniffin - updated : 6/10/2005<br>Cassandra L. Kniffin - updated : 4/12/2005<br>Victor A. McKusick - updated : 10/1/2003<br>Victor A. McKusick - updated : 12/13/2002<br>Victor A. McKusick - updated : 3/21/2002<br>Victor A. McKusick - updated : 11/9/2001<br>Orest Hurko - updated : 4/6/1998<br>Victor A. McKusick - updated : 8/1/1997
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Victor A. McKusick : 8/9/1996
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Thank you in advance for your generous support, <br />
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