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Axel Visel Links Cell Cycle-Inhibitor Genes to Risk of Heart Disease


A polymorphism in a non-coding stretch of chromosome 9p21 has been linked to an increased risk of developing coronary artery disease, say researchers at the Department of Energy's Lawrence Berkeley National Laboratory. This region regulates a pair of cell cycle-inhibitor genes, and the vascular cells of people with the variant divide and multiply more quickly than usual, leading to narrowed coronary arteries.

This variant is quite common, the study found: nearly 25 percent of the population is homozygous for the risk allele, while 50 percent of the population is heterozygous. According to Axel Visel, the first author of the Nature study reporting this work, this variant raises a homozygous individual's risk of developing coronary artery disease by about 30 percent to 40 percent above baseline, a moderate increase. "But considering such a large proportion of the population carries the risk allele, it potentially has a huge impact," Visel says.

Several studies over the past three years have sought to find genetic differences in people who developed coronary artery disease, as compared to people who did not develop the condition. These studies linked a region of 58,000 base pairs on chromosome 9p21 to heart disease, though the region is not associated with any known risks for coronary artery disease such as high cholesterol, high blood pressure, or diabetes.

In order to find out how this region is linked to the disease, Visel and his colleagues at LBNL knocked out the analogous region in mice to see how it would affect them. The expression level of two genes, Cdkn2a and Cdkn2b, located 100,000 base pairs away from the region, fell by about 90 percent in these knockout mice, and the smooth muscle cells of their aortas increased proliferation. The study shows that the region regulates these two genes and that the variant affects their expression.

Knowing how the mechanism works, it should be possible to pharmacologically regulate the risk of developing coronary artery disease, Visel says. "More work is clearly needed," he adds. "But knowing what the mechanism is might provide some clues as to how to affect the risk associated with these alleles."

Visel says the next step is to study how this variant regulates gene expression in humans.

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