by Steve Stiles
Washington, DC - Increasingly in explorations of why African Americans and whites with heart failure seem to respond differently to some drug therapies, genotype rules; race is a distraction.
A large, prospective study published online July 20, 2009 in the Journal of the American College of Cardiology suggests that much of the perceived differences in beta-blocker effectiveness, as well as variability in beta-blocker responses among African Americans, may be attributed to a couple of gene variants that affect beta receptors and their signaling pathways [1]. When those polymorphisms are controlled for, the supposed racial distinctions in beta-blocker response disappear, according to the authors, led by Dr Sharon Cresci (Washington University School of Medicine, St Louis, MO).
Of their 2460 patients with systolic heart failure followed for a median of 46 months, including 711 African Americans and 1749 whites, 2039 (about 82%) were treated with a beta blocker. Of those, 66% received carvedilol and 24% were given metoprolol.
All patients were genotyped for polymorphisms of beta-1 adrenergic receptor (ADRB1) Arg389gly (which encodes for beta receptors, the target of beta blockers) and for G-protein receptor kinase 5 (GRK5) Gln41Leu (which regulates beta-receptor signaling pathways). Both polymorphisms are "overrepresented" in African Americans compared with whites, Cresci et al explain, and "may play roles in determining individual clinical responses to beta blockade in heart failure."
G-protein receptor kinases desensitize and thereby "turn off" the beta receptors, primary author Dr Gerald W Dorn (Washington University School of Medicine) told heartwire. "It's the body's way of beta blocking."
Dorn and his colleagues previously found that 41% of a sample of African Americans carried at least one allele of the GRK5 variant, which was associated with significant improvement in heart-failure prognosis in the absence of beta-blocker therapy [2]. Similar survival times were seen in those without the variant who were taking beta blockers. But beta blockade in black patients with the variant didn't further prolong survival in this comparatively small study.
As described by heartwire in its coverage at the time, the polymorphism that is common in African Americans (but rare in whites) can make it appear that beta blockers don't improve their heart-failure survival. In effect, according to Dorn, the drugs are unable to extend the benefit already conferred by the GRK5 variant.
The apparent lack of beta-blocker effect masks the benefit observed in African Americans without the variant. They and the white patients showed similar survival gains on beta blockers.
The larger current study extends those findings in a more expansive population, Dorn said. In it, mortality was about 31% and was similarly reduced in whites and African Americans. The reduction in adjusted hazard ratio (HR) was significant in the former (HR 0.679, p=0.005) but not in the latter (HR 0.698, p=0.1).
Among the patients not taking beta blockers, the ADRB1 Gly389 variant was associated with a mortality HR of 1.98 (p=0.03) in whites, and the Leu41 variant of GRK5 was associated with a mortality HR of 0.325 (p<0.01) in African Americans.
Among those who were on beta blockers, African Americans genotyped as ADRB1 Gly389Gly GRK5 Gln41Gln showed a mortality reduction (HR 0.385, p=0.012) similar to that of whites with the same variants (HR 0.529, p=0.010), consistent with the smaller study's results.
Their data, write Cresci et al, show that the two polymorphisms can have a significant influence on heart-failure prognosis and outcomes "in the same manner as clinical risk modifiers." They also suggest that variations in apparent beta-blocker efficacy in their population associated with beta-receptor signaling-pathway gene polymorphisms, "rather than race, are the major factor contributing to apparent differences in beta-blocker treatment effect between [whites] and African Americans."
Sources
- Cresci S, Kelly RJ, Cappola TP, et al. Clinical and genetic modifiers of long-term survival in heart failure. J Am Coll Cardiol 2009; 54:432-444). DOI:10.1016/j.jacc.2009.05.009. Available at: http://content.onlinejacc.org.
- Liggett SB, Cresci S, Kelly RJ, et al. A GRK polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure. Nat Med 2008; 14:510-517.
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