Article abstract
Nature Medicine 14, 510 - 517 (2008)
Published online: 20 April 2008 | doi:10.1038/nm1750
A GRK5 polymorphism that inhibits 
-adrenergic receptor signaling is protective in heart failure
Stephen B Liggett1,6,7, Sharon Cresci2,7, Reagan J Kelly3,7, Faisal M Syed1, Scot J Matkovich2, Harvey S Hahn1, Abhinav Diwan1, Jeffrey S Martini4, Li Sparks1, Rohan R Parekh1, John A Spertus5, Walter J Koch4, Sharon L R Kardia3 & Gerald W Dorn II1,2
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.
- Department of Internal Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, Ohio 45267, USA.
- Center for Pharmacogenomics, Washington University, 660 S. Euclid Avenue, St. Louis, Missouri 63110, USA.
- Department of Epidemiology, School of Public Health, University of Michigan, 109 Observatory Road, Ann Arbor, Michigan 48109, USA.
- Center for Translational Medicine, Thomas Jefferson University, 1025 Walnut Street, Philadelphia, Pennsylvania 19107, USA.
- University of Missouri, 4401 Wornall Road, Kansas City, Missouri 64111, USA.
- Current address: Department of Medicine, Cardiopulmonary Genomics Program, University of Maryland, 20 Penn Street, Baltimore, Maryland 21201, USA.
- These authors contributed equally to this work.
Correspondence to: Gerald W Dorn II1,2 e-mail: gdorn@im.wustl.edu