August 16, 2010

Dozens of Genetic Variants Linked to Blood Lipid Levels

Illustration of the inside of a man's chest Darren Hopes, Wellcome Images

Scientists have uncovered the largest set of genetic variants linked to blood lipid levels, which can contribute to heart disease. The findings could lead to more targeted therapies and a better understanding of how heredity can affect cardiovascular health.

Heart disease is the nation’s number 1 killer and a significant cause of disability. A major risk factor for heart disease is the blood concentration of fatty molecules called lipids, including cholesterol and triglycerides. Lifestyle factors—such as smoking, diet and physical activity—affect lipid levels. Genetics are also known to play an important, but still poorly understood, role.

Two years ago, scientists analyzed the genomes of about 20,000 people of European ancestry and identified more than 30 genetic variants linked to blood lipids. In a new study, an international research team scanned the genomes of more than 100,000 people of European ancestry. They also searched for specific variants in more than 30,000 people from different ethnic groups. The study received primary funding from NIH's National Heart, Lung and Blood Institute (NHLBI), with additional support from NIH’s National Human Genome Research Institute (NHGRI), National Institute on Aging (NIA) and other NIH components. The results were reported in the August 5, 2010, issue of Nature.

The scientists identified 95 genetic variants linked to blood cholesterol and triglyceride levels in women and men of many ethnic backgrounds. Some of the genes are known targets of cholesterol-lowering drugs. Another 59 variants had not been previously linked to lipid metabolism and so may provide new clues for developing more targeted therapies. The researchers found that several of the newly identified variants were also associated with coronary artery disease. Some of the 95 variants are in non-protein-coding regions of the genome.

In a companion paper—also funded by NHLBI—a research team took a closer look at how one genetic variant affects blood lipid metabolism in mice. The researchers focused on a non-coding region of chromosome 1 that had previously been linked to heart attack and high levels of LDL ("bad" cholesterol) in humans. The variant is common in people of African American, Hispanic, Asian Indian and Chinese ancestry.

The scientists found that the genetic variant creates a binding site along the genome for a transcription factor protein, which can turn genes on or off. When the transcription factor binds to the site, it alters the expression of certain genes in the liver, including the SORT1 gene. By modifying the expression of this gene in mice, the scientists uncovered the molecular mechanisms that lead to changes in blood levels of LDL and other lipids. The finding demonstrates how a non-coding variant can affect the levels of blood lipids that contribute to heart disease.

"Genetic studies that survey a wide variety of human populations are a powerful tool for identifying hereditary factors in health and disease," says NIH Director Dr. Francis S. Collins, a coauthor of the large-scale genome analysis. These findings provide insights into why some people are more prone to higher levels of cholesterol and other blood lipids, and may one day lead to novel ways of preventing and treating heart disease.

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