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Rare mutations can significantly increase risk factor for heart disease

Certain rare gene mutations can contribute significantly to low levels of a beneficial form of cholesterol in the blood, researchers have found. Low levels of this cholesterol, known as high-density lipoprotein (HDL), are a major risk factor for heart disease.

Gene mutations previously known to affect HDL levels had small effects individually, and it was thought many such mutations needed to accumulate before HDL levels were significantly reduced. The new finding, however, demonstrates that mutations in a few genes can be sufficient to affect blood cholesterol levels. According to the researchers, the strategy used in this study can be generalized to analyze the role of rare variations in candidate genes in other clinically important complex human traits.

Led by Howard Hughes Medical Institute investigator Helen H. Hobbs, who is at the University of Texas Southwestern Medical Center at Dallas, the researchers published their findings in the August 6, 2004, issue of the journal Science. Hobbs' colleagues from the University of Texas Southwestern and the University of Ottawa Heart Institute were coauthors on the paper.

HDL is important for preventing heart disease because it transports cholesterol in the blood back to the liver, leading to its removal from the body and preventing its buildup on artery walls. The level of HDL in the blood is a complex trait, influenced to varying degrees by many genes, as well as environmental and lifestyle factors such as diet and exercise.

Previously, researchers believed that the genetic component of this trait depended primarily on the cumulative effect of many common genetic variations, each of which influenced HDL levels in a small way. However, rare variations with stronger effects are also likely to be involved. "What we wanted to know," Hobbs said, "was how much do single gene defects with major effects contribute to complex traits?"

Although mutations with such a strong effect on overall HD
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Contact: Jennifer Michalowski
michalow@hhmi.org
301-215-8576
Howard Hughes Medical Institute
16-Aug-2004


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