Genetic variations may modify cardiovascular benefit of aspirin

Aspirin is the gold standard for antiplatelet therapy and a daily low-dose aspirin is widely prescribed for the prevention of cardiovascular disease.

Now, a new study suggests that common genetic variation in the gene for catechol-O-methyltransferase (COMT) may modify the cardiovascular benefit of aspirin, and in some people, may confer slight harm. The findings, led by investigators at Beth Israel Deaconess Medical Center (BIDMC) and Brigham and Women's Hospital (BWH) appear online in the American Heart Association journal Arteriosclerosis, Thrombosis, and Vascular Biology.

"This is one of the few cases where you can identify a single genetic polymorphism which has a significant interaction with aspirin such that it affects whether or not it protects against cardiovascular disease," says first author Kathryn Hall, PhD, MPH, an investigator in the Division of General Medicine and Primary Care at BIDMC and Research Fellow at Harvard Medical School.

COMT is a key enzyme in the metabolism of catecholamines, a group of hormones that include epinephrine, norepinephrine, and dopamine. "These hormones are implicated in a broad spectrum of disorders, including hypertension," explains Hall, "We were initially interested in finding out if the COMT gene affected people's susceptibility to incident cardiovascular disease such as myocardial infarction or ischemic stroke." Knowing that aspirin is commonly prescribed for the prevention of incident cardiovascular disease, the investigators also wanted to learn if genetic variation in COMT would influence aspirin's potential benefit.

To answer these questions, the researchers used data from the Women's Genome Health Study, a cohort of over 23,000 women who were followed for 10 years in a randomized double-blind, placebo-controlled trial of low-dose aspirin or vitamin E for the primary prevention of incident cardiovascular disease. Their analysis focused on val158met, a common variant in the COMT gene: Individuals who are homozygous for the enzyme's high-activity valine form, the "val/vals," have been shown to have lower levels of catecholamines compared to individuals who are homozygous for the enzyme's low-activity methionine form, the "met/mets,". The val/met heterozygotes are in between.

"When we examined women in the placebo arm of the trial, we found that the 23 percent of the women who were 'val/vals' were naturally protected against incident cardiovascular disease," explains senior author Daniel I. Chasman, PhD, a genetic epidemiologist in the Division of Preventive Medicine at Brigham and Women's Hospital and Associate Professor of Medicine at Harvard Medical School. "This finding, which was replicated in two other population-based studies, was in itself of significant interest." But, he adds, the investigation further revealed the surprising discovery that when the women with the val/val polymorphism were allocated to aspirin, this natural protection was eliminated.