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

Nature Medicine volume 14, pages 510–517 (2008)Cite this article

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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Figure 1: Characteristics of CHO cells and mouse hearts expressing GRK5-Gln41 (Q41) and GRK5-Leu41 (L41).
Figure 2: Cardiac expression of GRK5-L41, but not GRK5-Q41, confers resistance to catecholamine-induced cardiomyopathy.
Figure 3: Prospective analysis of the interaction between GRK5 polymorphism and β-blockade as a determinant of heart failure outcome in African Americans.

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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.

Author information

Author notes

  1. Stephen B Liggett

    Present address: Current address: Department of Medicine, Cardiopulmonary Genomics Program, University of Maryland, 20 Penn Street, Baltimore, Maryland 21201, USA.,

  2. Stephen B Liggett, Sharon Cresci and Reagan J Kelly: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, 45267, Ohio, USA

    Stephen B Liggett, Faisal M Syed, Harvey S Hahn, Abhinav Diwan, Li Sparks, Rohan R Parekh & Gerald W Dorn II

  2. Center for Pharmacogenomics, Washington University, 660 S. Euclid Avenue, St. Louis, 63110, Missouri, USA

    Sharon Cresci, Scot J Matkovich & Gerald W Dorn II

  3. Department of Epidemiology, School of Public Health, University of Michigan, 109 Observatory Road, Ann Arbor, 48109, Michigan, USA

    Reagan J Kelly & Sharon L R Kardia

  4. Center for Translational Medicine, Thomas Jefferson University, 1025 Walnut Street, Philadelphia, 19107, Pennsylvania, USA

    Jeffrey S Martini & Walter J Koch

  5. University of Missouri, 4401 Wornall Road, Kansas City, 64111, Missouri, USA

    John A Spertus

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Contributions

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.

Corresponding author

Correspondence to Gerald W Dorn II.

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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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