Abstract

-adrenergic receptor (AR) blockade is a standard therapy for cardiac failure and ischemia. G protein–coupled receptor kinases (GRKs) desensitize 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 AR blockade, GRK5-Leu41 protected against experimental catecholamine-induced cardiomyopathy. Human association studies showed a pharmacogenomic interaction between GRK5-Leu41 and -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 AR desensitization of excessive catecholamine signaling by GRK5-Leu41 provides a 'genetic -blockade' that improves survival in African Americans with heart failure, suggesting a reason for conflicting results of -blocker clinical trials in this population.

1. Department of Internal Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, Ohio 45267, USA.
2. Center for Pharmacogenomics, Washington University, 660 S. Euclid Avenue, St. Louis, Missouri 63110, USA.
3. Department of Epidemiology, School of Public Health, University of Michigan, 109 Observatory Road, Ann Arbor, Michigan 48109, USA.
4. Center for Translational Medicine, Thomas Jefferson University, 1025 Walnut Street, Philadelphia, Pennsylvania 19107, USA.
5. University of Missouri, 4401 Wornall Road, Kansas City, Missouri 64111, USA.
6. Current address: Department of Medicine, Cardiopulmonary Genomics Program, University of Maryland, 20 Penn Street, Baltimore, Maryland 21201, USA.
7. These authors contributed equally to this work.

Correspondence to: Gerald W Dorn II^1,2 e-mail: gdorn@im.wustl.edu

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