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<h2 class="element-invisible">You are here</h2><div class="breadcrumb"><a href="/">Home</a> » <a href="/news-events">News & Events</a> » <a href="/news-events/nih-research-matters">NIH Research Matters</a></div> <div class="l-region l-region--section-header">
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<p class="publishdate"><span property="dc:date" datatype="xsd:dateTime" content="2014-06-30T00:00:00-04:00" class="date-display-single">June 30, 2014</span></p><div class='syndicate'><h1>Rare Mutations Reduce Heart Disease Risk</h1><div class="media-float-right"><div class="ds-1col file file-image file-image-jpeg view-mode-floated_media clearfix">
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</div><p>Researchers identified variations in a gene that are associated with lower triglyceride levels and a reduced risk of coronary heart disease. The findings may suggest new directions for development of therapeutics.</p>
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<p>Coronary heart disease is the leading cause of death in the United States. Levels of certain types of lipids (fats) that circulate throughout the body have been linked to heart disease risk. For example, high levels of low-density lipoprotein (LDL) cholesterol are associated with a greater risk for heart disease. Conversely, high levels of high-density lipoprotein (HDL) cholesterol are associated with a lower risk of heart disease. High levels of triglycerides, another type of lipid in the blood, also may raise the risk of coronary heart disease.</p>
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<p>A large team of researchers led by Dr. Sekar Kathiresan of Massachusetts General Hospital and Broad Institute explored the relationship among genetic mutations, plasma triglycerides, and coronary heart disease. The study was part of the Exome Sequencing Project of NIH’s National Heart, Lung, and Blood Institute (NHLBI). The overall goal of this project is to sequence protein-coding regions (exomes) to discover novel genes and mechanisms contributing to heart, lung, and blood disorders.</p>
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<p>The team sequenced over 18,000 genes from participants of European or African ancestry who were enrolled in 7 large studies, including the Framingham Heart Study and the Women’s Health Initiative. The analysis appeared online on June 18, 2014, in <em>New England Journal of Medicine.</em></p>
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<p>The researchers identified rare mutations (DNA sequence changes) in the gene encoding apolipoprotein C3 (<em>APOC3</em>) that were associated with lower plasma triglyceride levels. About 1 in 150 of the 3,734 study participants had at least 1 of 4 specific mutations that disrupt function in this gene. These participants had 39% lower triglyceride levels, 22% higher HDL cholesterol levels, 16% lower LDL cholesterol levels, and 46% lower circulating APOC3 levels compared to participants who did not have any of these genetic misspellings.</p>
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<p>The team next evaluated the association between <em>APOC3 </em>mutations and the risk of coronary heart disease in about 111,000 participants of European, African, and Hispanic ancestry. They found that people who had at least 1 of the 4 mutations had a 40% lower risk of coronary heart disease than those who didn’t.</p>
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<p>The researchers note that additional work will be needed to understand the mechanisms by which APOC3 function might be linked to coronary heart disease.</p>
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<p>“HDL and triglycerides are both correlated with heart attack, and have an inverse relationship with one another—the lower the HDL, the higher the triglycerides. It has long been presumed that low HDL is the causal factor in heart disease, and triglycerides are along for the ride. But our genetic data indicate that the true causal factor may not be HDL after all, but triglycerides,” Kathiresan says. “Our study really reinvigorates the idea of lowering triglycerides and specifically, by blocking APOC3, as a viable therapeutic strategy for addressing residual risk.”</p>
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<p>—by Carol Torgan, Ph.D.</p>
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</div><h2 class="label-above">Related Links</h2><ul class="spaced print-urls"><li><a href="https://www.nih.gov/news-events/nih-research-matters/questions-about-hdl-cholesterol" target="_top">Questions About HDL Cholesterol</a></li><li><a href="https://www.nih.gov/news-events/nih-research-matters/duration-obesity-may-affect-heart-disease" target="_top">Duration of Obesity May Affect Heart Disease</a></li><li><a href="https://www.nih.gov/news-events/nih-research-matters/dozens-genetic-variants-linked-blood-lipid-levels" target="_top">Dozens of Genetic Variants Linked to Blood Lipid Levels</a></li><li><a href="http://www.nhlbi.nih.gov/health/health-topics/topics/cad/" target="_top">Coronary Heart Disease</a></li><li><a href="https://esp.gs.washington.edu/drupal/" target="_top">NHLBI Grand Opportunity Exome Sequencing Project (ESP)</a></li></ul><p class="footnote"><strong class="label-inline">References: </strong><a href="http://www.ncbi.nlm.nih.gov/pubmed/24941081">Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease.</a> The TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute. <em>N Engl J Med</em>. 2014 Jun 18. [Epub ahead of print]. PMID: 24941081.</p><p class="footnote"><strong class="label-inline">Funding: </strong>NIH’s National Heart, Lung, and Blood Institute (NHLBI); Russell and Diana Hawkins Family Foundation Discovery Fellowship; British Heart Foundation; Canadian Institutes of Health Research; Massachusetts General Hospital; Donovan Family Foundation; Merck; Fondation Leducq; Swedish Heart–Lung Foundation; and the Regione Emilia-Romagna.</p>
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<p><a href="https://www.nih.gov/news-events/nih-research-matters/risk-future-burden-dementia-united-states">Risk and future burden of dementia in the United States </a></p>
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<p><a href="https://www.nih.gov/news-events/nih-research-matters/complete-wiring-map-adult-fruit-fly-brain">Complete wiring map of an adult fruit fly brain</a></p>
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<p><strong>Editor:</strong> Harrison Wein, Ph.D.</p>
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<p><strong><em>NIH Research Matters </em></strong>is a weekly update of NIH research highlights reviewed by NIH’s experts. It's published by the <a href="/institutes-nih/nih-office-director/office-communications-public-liaison">Office of Communications and Public Liaison</a> in the <a href="/institutes-nih/nih-office-director">NIH Office of the Director</a>.</p>
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