A GRK5 polymorphism that inhibits β-adrenergic receptor signaling is protective in heart failure

beta-adrenergic receptor (beta AR) blockade is a standard therapy for cardiac failure and ischemia. G protein-coupled receptor kinases ( GRKs) desensitize beta ARs, suggesting that genetic GRK variants might modify outcomes in these syndromes. Re-sequencing of GRK2 and GRK5 revealed a nonsynonymous polymorphism of GRK5, common in African Americans, in which leucine is substituted for glutamine at position 41. GRK5-Leu41 uncoupled isoproterenol-stimulated responses more effectively than did GRK5-Gln41 in transfected cells and transgenic mice, and, like pharmacological bAR blockade, GRK5-Leu41 protected against experimental catecholamine-induced cardiomyopathy. Human association studies showed a pharmacogenomic interaction between GRK5- Leu41 and beta-blocker treatment, in which the presence of the GRK5-Leu41 polymorphism was associated with decreased mortality in African Americans with heart failure or cardiac ischemia. In 375 prospectively followed African-American subjects with heart failure, GRK5- Leu41 protected against death or cardiac transplantation. Enhanced bAR desensitization of excessive catecholamine signaling by GRK5- Leu41 provides a 'genetic beta-blockade' that improves survival in African Americans with heart failure, suggesting a reason for conflicting results of beta-blocker clinical trials in this population.