Baltimore, MD - Around 40% of blacks carry a genetic variant that appears to act like a natural beta blocker and seems to protect them after heart failure, prolonging their lives, new research has shown [1]. The findings may help explain why beta blockers don't appear to benefit some African Americans, say Dr Stephen B Liggett (University of Maryland, Baltimore) and colleagues in a study published online April 20, 2008 in Nature Medicine.

While white patients with heart failure participating in clinical studies of beta blockers have shown clear benefit from the drugs, the effects of beta blockers in African Americans have been ambiguous. Second author Dr Sharon Cresci (Washington University, St Louis, MO) told heartwire: "I think this is so exciting. I believe this gene has significantly contributed to the discrepancies that have been found in such studies. If researchers were able to go back and genotype patients from their studies, it would probably help clarify some of their findings."

But she and her coworkers stress that it is too early, on the basis of just this one study, to advocate not prescribing beta blockers to blacks who carry the genetic variant. "The research is a step toward individualized therapy tailored to personal genetic makeup," she says. "I think we are working toward genotyping patients for many genetic variants and I believe we are on the threshold of that, but we are not there yet. We need a prospective study."

The researchers explain in their paper that the heart has two forms of G-protein-coupled receptor kinase (GRK): GRK2 and GRK5. They sequenced the DNA of 96 people of European American, African American, or Chinese descent to look for differences and found that most people, no matter their race, had exactly the same gene sequence encoding GRK2 or GRK5.

But there was one common variation, called GRK5-Leu41, in which leucine is substituted for glutamine at position 41 in GRK5—and 41% of African Americans carried at least one allele of this variant.

To determine the effect of the GRK5-Leu41 variant, the team then studied the course of progression of heart failure in 375 African American patients. They looked at survival time or time to heart transplant, comparing people with the variant and those without. Some of these patients were taking beta blockers and some were not.

In patients not taking beta blockers, those with the variant lived almost twice as long as those with the more common version of the GRK5 gene. In those taking beta blockers, the drugs prolonged life to the same degree as the protective GRK5 variant but did not further increase the already improved survival of those with the variant.

"These results offer an explanation for the confusion that has occurred in this area since clinical trials of beta blockers began," senior author Dr Gerald W Dorn (Washington University) said in a press release from the university [2].

"By mimicking the effect of beta blockers, the genetic variant makes it appear as if beta blockers aren't effective in these patients," he explains. "But although beta blockers have no additional benefit in heart-failure patients with the variant, they are equally effective in white and African American patients without the variant."

"Our study demonstrates a mechanism that should lay to rest the question about whether beta blockers are effective in African Americans—they absolutely are in those who don't have this genetic variant," Dorn adds.

Cresci said the feeling among the group was that it is too soon to advocate testing blacks with heart failure for this specific genetic variant to decide whether or not they should take beta blockers. "Beta blockers are very safe, and they have a variety of effects that we don't completely understand. We're not able to say you can take patients off beta blockers based on one or two polymorphisms. That seems a little risky at this point."

However, she said that the team is conducting more investigation in this area, and she could not rule out that it might be possible to tailor therapy to individuals using this variant in the future.

"This is a very significant step toward individualized therapy. Medical research is working to identify many genetic variants that someday can ensure that patients receive the medications that are most appropriate for them. Right now, we know one variant that influences beta-blocker efficacy, and we are continuing our research into this and other relevant genetic variants."

She adds that GRK5 is also a potential therapeutic target in patients with heart failure.