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

Nat Med. 2008 May;14(5):510-7. doi: 10.1038/nm1750. Epub 2008 Apr 20.

Abstract

Beta-adrenergic receptor (betaAR) blockade is a standard therapy for cardiac failure and ischemia. G protein-coupled receptor kinases (GRKs) desensitize betaARs, 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 betaAR 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 betaAR 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenergic beta-Antagonists / pharmacology
  • Adrenergic beta-Antagonists / therapeutic use
  • African Americans / genetics
  • Animals
  • Base Sequence
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • European Continental Ancestry Group / genetics
  • G-Protein-Coupled Receptor Kinase 5 / genetics*
  • G-Protein-Coupled Receptor Kinase 5 / metabolism
  • Gene Frequency
  • Heart Failure / drug therapy
  • Heart Failure / genetics*
  • Humans
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Pharmacogenetics / methods
  • Polymorphism, Single Nucleotide / genetics*
  • Prospective Studies
  • Receptors, Adrenergic, beta / metabolism*
  • Sequence Analysis, DNA
  • Signal Transduction / genetics*
  • United States

Substances

  • Adrenergic beta-Antagonists
  • Receptors, Adrenergic, beta
  • G-Protein-Coupled Receptor Kinase 5
  • GRK5 protein, human