Gene Variation Raises Heart Disease Risk for African-Americans

A gene involved in blood clotting is linked to a six-fold increase in risk for heart disease in African-Americans. The first prospective study to examine the gene as it relates to heart disease was published in Circulation: Journal of the American Heart Association.

"Our findings underscore the importance of studying genetic risk factors by ethnic group," says Dr. Kenneth K. Wu, lead author of the study and professor and director of the Hematology and Vascular Biology Research Center at The University of Texas Health Science Center at Houston. "They also provide a genetic basis for differential risk factors of heart attacks between African-Americans and Caucasians."

The gene in the study is the blueprint for a protein called thrombomodulin, which is found in the lining of the blood-vessel walls. The protein converts the enzyme thrombin from a clotting agent into an anti-clotting agent. A common variance in the thrombomodulin gene occurs when alanine (an amino acid) is replaced by valine at amino acid position 455. This shift in gene structure has been previously associated with heart-attack risk.

Genes give instructions on how amino acids link together to form proteins. Any shift in the order in which amino acids are linked can cause the protein to function abnormally. Reduced levels of normal thrombomodulin as a result of the altered gene may cause an increased tendency for blood vessel damage and blood clots.

"We have identified a genetic marker for predicting increased heart attack risk in African-Americans. Our results show that a single amino acid change in the thrombomodulin gene is an independent risk factor for coronary heart disease in blacks," says Dr. Wu, who also holds the Roy and Phyllis Huffington Chair in Gerontology at the UT-Houston Medical School.

The same small shift in the structure of the thrombomodulin gene was not associated with coronary heart disease risk in white individuals.

Researchers recently analyzed the association of this structure with coronary heart disease in a prospective followup of the Atherosclerosis Risk in Communities study. ARIC is a population-based study that recruited 15,792 men and women ages 45-64 from four different communities in the United States. Baseline examinations, including blood pressures and samples of blood and DNA, were conducted between 1987 and 1989. Participants were re-examined on a three-year cycle.

Researchers identified 467 individuals who developed coronary heart disease during an average of five years of follow-up. Thrombomodulin genotypes at the 455 position were determined in 376 of these cases (23 percent black, 77 percent white), as well as a reference sample of 461 study participants. Each person has two copies of the thrombomodulin gene (one from each parent).

African-Americans with at least one copy of the altered form of the gene had a 6.1 times greater risk for coronary heart disease after adjustment for other risk factors.

The unaltered genotype - no copies of the altered gene - was more common in those with no heart disease. Ninety-eight out of 105 (93 percent) of healthy blacks and 237 out of 356 (67 percent) of healthy whites had the unaltered genotype.

Why the thrombomodulin-455 structure is associated with higher heart disease risk in blacks than whites is not clear. Dr. Wu says one possible explanation is that the gene may act differently in blacks than whites.

"It is likely that the valine structure is a risk factor for heart attacks in all blacks in the United States, since ARIC is a population-based study. However, I would like to caution that the number of African-Americans with coronary heart disease in our study group is relatively small when compared to the number of white cases," says Dr. Wu. The group is analyzing a large number of cases to substantiate the results of this study.

The research team plans to study the association of heart attacks and stroke with other genes that affect clotting.

Co-authors include Drs. Nena Aleksic Chul Ahn and Harinder Juneja, of The University of Texas Medical School at Houston; Dr. Eric Boerwinkle of The University of Texas School of Public Health at Houston; and Dr. Aaron R. Folsom of the University of Minnesota School of Public Health.

This study was supported by the National Heart, Lung and Blood Institute of the National Institutes of Health.

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©2006 Texas Medical Center

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