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<p class="publishdate"><span property="dc:date" datatype="xsd:dateTime" content="2010-03-01T00:00:00-05:00" class="date-display-single">March 1, 2010</span></p><div class='syndicate'><h1>How Junk DNA Affects Heart Disease</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 have figured out how a mysterious DNA region previously tied to heart disease may exert its effect. The discovery could open the door to new prevention and treatment strategies.</p>
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<p>Heart disease is the leading cause of death in the United States and a major cause of disability. Genome-wide association studies, which scan the genomes of large numbers of people to find genetic variations associated with disease, recently linked gene variations on human chromosome 9p21 with an increased risk for heart disease. The variants only moderately raise the risk of disease, but they’re very common and so may make a significant contribution to heart disease in the population.</p>
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<p>How these variants affect heart disease has been a mystery. They aren’t associated with known risk factors, such as blood lipid levels, hypertension or diabetes. They’re also within a 58,000-base stretch of so-called "junk" DNA, which contains no known protein-coding genes. The human genome has about 3 billion human DNA base pairs, with genes making up only a small fraction of that—about 2%. Little is known about the function of the remaining 98% that doesn’t code for proteins.</p>
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<p>Scientists from the U.S. Department of Energy’s Lawrence Berkeley National Laboratory led by Dr. Len A. Pennacchio set out to try to understand how this non-coding interval between genes affects heart disease. To do this, they genetically engineered mice to completely lack the interval. The study, partly funded by NIH’s National Heart, Lung and Blood Institute (NHLBI) and National Human Genome Research Institute (NHGRI), appeared in the advance online edition of <em>Nature </em>on February 21, 2010.</p>
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<p>The researchers looked at genes near the deleted interval and found that 2 genes—<em>Cdkn2a</em> and <em>Cdkn2b</em>—were expressed at 10-fold lower levels in heart tissue of altered mice. <em>Cdkn2a</em> and <em>Cdkn2b</em> belong to a family of "cell cycle" genes, which are involved in regulating cell proliferation. When the researchers examined how muscle cells taken from the heart grew in the laboratory, they found that cells lacking the interval multiplied faster than controls and kept proliferating after the control cells had stopped.</p>
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<p>When the scientists placed 40 of the genetically altered mice and 40 controls on a high-fat, high-cholesterol diet for 20 weeks, blood lipid levels rose to similar levels in both groups of mice. There were also no significant differences in fatty deposits in arteries. However, the diet caused substantially more deaths among the mice lacking the non-coding interval. These results suggest that the interval exerts its effect through a mechanism independent of blood lipid levels and other known risk factors.</p>
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<p>"We show that this non-coding interval affects the expression of 2 cell cycle inhibitor genes located almost 100,000 base pairs away from the deletion," Pennacchio says. "We believe that something goes awry in variants of this interval, causing vascular cells to divide and multiply more quickly than usual." That may increase the risk for heart disease, the researchers speculate, by narrowing coronary arteries.</p>
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<p>"Non-coding DNA is a huge area of the genome, waiting to be explored, which could have huge dividends for understanding and treating disease," Pennacchio adds.</p>
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<p>—by Harrison Wein, Ph.D.</p>
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</div><h2 class="label-above">Related Links</h2><ul class="spaced print-urls"><li><a href="http://www.nhlbi.nih.gov/health/public/heart/index.htm" target="_top">Heart and Vascular Diseases</a></li><li><a href="http://www.nih.gov/researchmatters/march2009/03232009genome.htm" target="_top">DNA Terrain Affects Function in Human Genome</a></li></ul>
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<p><strong>Editor:</strong> Harrison Wein, Ph.D.</p>
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<p><strong>Assistant Editors:</strong> Vicki Contie and Brian Doctrow, 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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<p>ISSN 2375-9593</p>
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