NEW YORK (GenomeWeb News) – Many African-Americans carry a genetic polymorphism that acts like a built-in beta blocker drug and improves survival after heart failure, according to new research.
Using sequencing and genotyping methods, researchers from the University of Cincinnati, Washington University in St. Louis, and elsewhere identified a genetic polymorphism that creates a “genetic beta blockage,” mimicking the effect of heart drugs called beta blockers. In a paper published in Nature’s advanced online edition yesterday, the team reported that roughly 40 percent of African-Americans carry the beneficial genetic variation — a finding that may explain why it’s notoriously difficult to predict the effect of beta blockers in African-American patients.
“By mimicking the effect of beta blockers, the genetic variant makes it appear as if beta blockers aren’t effective in these patients,” senior author Gerald Dorn, director of Washington University’s Center for Pharmacogenomics, said in a statement. “But although beta blockers have no additional benefit in heart failure patients with the variant, they are equally effective in Caucasian and African-American patients without the variant.”
Heart failure, an inability of the heart to pump sufficient blood to the body, affects about 5 million Americans and accounts for some 300,000 deaths annually in the US. It can occur following a heart attack or hypertension or may arise without any apparent cause. During and after heart failure, the body typically produces catecholamines — “fight-or-flight” hormones such as adrenaline — in excess. This kick-starts the heart, but ultimately puts additional stress on it, weakening it further.
Beta blockers, drugs that block the beta adrenergic receptor, are the most common treatment following heart failure. By dampening catecholamine response, they decrease blood pressure and slow heart rate — easing stress on the heart. But in past clinical trials, Caucasian patients have shown more obvious benefits from taking beta blockers than their African-American counterparts.
Now, Dorn and his team provide evidence that explains why such differences may exist. They resequenced two GRK genes, GRK2 and GRK5, in 40 individuals of European descent, 40 African-American individuals, and 16 individuals of Chinese descent. The genes code for enzymes that decrease beta adrenergic sensitivity, tempering the heart’s response to catecholamines.
While the researchers did not find any differences in the GRK2 gene, they did identify a GRK5 polymorphism — called GRK5-Leu41 — in which a leucine is substituted for glutamine. While the GRK5-Leu41 mutation was rare in those of European or Chinese descent, the researchers found that about 40 percent of the African-Americans tested carry this beneficial GRK5 variant.
The researchers’ experiments in cell lines and mouse models indicated that the variant leads to decreased catecholamine-related signaling and greater desensitization to beta-adrenergic receptor stimulated heart contractions. In the animal models, the GRK5-Leu41 variant protected mice from increased heart size and shape changes in response to hormone signaling. This suggests the genetic variant acts in the same way that beta blockers do, decreasing the catecholamine hormone response and easing stress on the heart.
To test this, Dorn and his colleagues took several approaches to determine the prevalence and effect of the GRK5-Leu41 variant. First, they genotyped GRK5 in thousands of individuals: 568 European-Americans and 242 African-Americans who had experienced heart failure and 580 European-Americans and 242 African-Americans with acute cardiac ischemia — a partial or complete blockage that decreases blood flow to the heart. They compared these with a control group of 406 and 107 healthy European-American and African-American individuals, respectively.
They found that the GRK5-Leu41 variant was not only more common in African-Americans, but also showed a pharmacogenomic interaction with beta-blocker treatment — an association that wasn’t present in those with the GRK5-Gln41 variant.
During a prospective study carried out at the University of Cincinnati, the team followed 375 African-American patients with or without the GRK5-Leu41 variant who had experienced heart failure. Some were taking beta blockers while others were not. When they compared the amount of time patients survived without needing a heart transplant, the team found that the survival rate is roughly equivalent for those with the variant who don’t take beta blockers and others without the variant who do.
Among patients who weren’t taking beta-blockers, those with the GRK5-Leu41variant survived about twice as long as those other patients.
“This is a step toward individualized therapy,” co-lead author Sharon Cresci, a cardiovascular researcher at Washington University, said in a statement. “Right now, we know one variant that influences beta blocker efficacy, and we are continuing our research into this and other relevant genetic variants.”