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

Stephen B. Liggett, Sharon Cresci, Reagan J. Kelly, Faisal M. Syed, Scot J. Matkovich, Harvey S. Hahn, Abhinav Diwan, Jeffrey S. Martini, Li Sparks, Rohan R. Parekh, John A. Spertus, Walter J. Koch, Sharon L.R. Kardia, Gerald W. Dorn

Research output: Contribution to journalArticlepeer-review

249 Scopus citations

Abstract

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

Original languageEnglish
Pages (from-to)510-517
Number of pages8
JournalNature medicine
Volume14
Issue number5
DOIs
StatePublished - May 2008

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