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.
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Acknowledgements
Supported by US National Heart, Lung, and Blood Institute Special Clinical Centers of Research in Heart Failure grants P50 HL77101 and HL77113 and by R01 HL87871.
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S.B.L., adenylyl cyclase studies and manuscript preparation; S.C., ischemic cohort genotyping; R.J.K., statistical analysis and manuscript preparation; F.M.S., clinical heart failure studies; S.J.M., transgenic mouse studies; H.S.H., clinical heart failure and transgenic mouse studies; A.D., clinical heart failure and transgenic mouse studies; J.S.M., rhodopsin kinase studies; L.S., heart failure cohort genotyping; R.R.P., polymorphism discovery and heart failure cohort genotyping; J.A.S., clinical ischemia studies; W.J.K., supervised studies; S.L.R.K., supervised statistical analyses; G.W.D. II, conceived and directed polymorphism discovery, heart failure genomics and transgenic mouse studies and prepared manuscript.
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Liggett, S., Cresci, S., Kelly, R. et al. A GRK5 polymorphism that inhibits β-adrenergic receptor signaling is protective in heart failure. Nat Med 14, 510–517 (2008). https://doi.org/10.1038/nm1750
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DOI: https://doi.org/10.1038/nm1750
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