Gene variants and beta-blockers associated with increased risk of death

Patients with certain gene variants who were prescribed beta-blocker drugs after acute coronary syndrome (ACS) had an increased risk of death over the next three years, according to a study in the September 28 issue of Journal of the American Medical Association (JAMA).

Beta-blockers are drugs that block the action of beta-adrenergic substances such as adrenaline in the "sympathetic" portion of the nervous system – relieving stress on the heart, slowing the heartbeat, and reducing blood vessel contraction in the heart, brain, and throughout the body, according to background information in the article. Previous data support an association between variants of the ADRB1 and ADRB2 genes and response to beta-blocker therapy, but no relationship between these variants and the survival of patients receiving beta-blocker therapy has been reported.

David E. Lanfear, M.D., formerly of Washington University School of Medicine, St. Louis, and colleagues conducted a prospective cohort study of 735 ACS patients admitted to two medical centers between March 2001 and October 2002. The ACS patients were diagnosed with either myocardial infarction (heart attack) or unstable angina (an accelerating pattern of chest pain that lasts longer and is less responsive to medication than stable angina). Among those enrolled in the study, 597 were discharged from the hospital with beta-blocker therapy. DNA testing was conducted to find out if the patients carried any of four common variants of the ADRB1 and ADRB2 genes (ADRB1 1165 CG, 145 AG; ADRB2 46 GA, 79 CG).

The researchers followed the study patients for three years after discharge. There were 84 deaths during follow-up.

"There was a significant association between ADRB2 genotype and three-year mortality among patients prescribed beta blocker therapy," the authors report.

"For the 79 CG polymorphism, … three-year mortality rates were 16 percent (35 deaths), 11 percent (27 deaths), and six percent (four deaths) for the CC, CG, and GG genotypes, respectively," they write. "For the ADRB2 46 GA polymorphism, three-year … mortality estimates were ten percent (17 deaths), ten percent (28 deaths), and 20 percent (20 deaths) for the GG, GA, and AA genotypes, respectively."

No increased mortality risk was observed in patients with the same ADRB2 gene variants who were not prescribed beta-blockers. No association of the ADRB1 variants with mortality was observed in either the beta-blocker group, or in the patients who were not prescribed beta-blockers.

The researchers believe this initial description of an association of ADRB2 genotype with survival among patients receiving beta-blocker therapy has potentially important implications.

"Among ACS patients discharged with beta-blocker therapy, we have identified a genetic association with survival that can assist in the risk stratification of patients," they write. "Specifically, the 79 CC and 46 AA groups (39 percent and 16 percent, respectively, of our population) are at high risk for long-term mortality and may need additional treatments to optimize their prognosis."

"We strongly encourage further replication of our findings in distinct patient cohorts so that the potential benefit or harm of beta-blocker therapy within specific ADRB2 genotype groups can be definitively demonstrated," the authors conclude. "With further validation, pharmacogenetic targeting of beta-blocker therapy may be an opportunity to further improve ACS care and outcomes."