G-Protein Receptor Kinase-5 Polymorphism Influences Therapeutic Efficacy of β-Blockers in Heart Failure

Abstract

Genetic polymorphisms that alter adrenergic receptor (AR) function are risk modifiers for heart failure, and pharmacological βAR blockade prolongs life in heart failure patients. Since signal transduction by βAR is regulated by G-protein receptor kinases (GRK), we hypothesized that gene variants of cardiac-expressed GRKs would affect progression of heart failure or therapeutic response to β-blockade. Methods: Non-synonymous polymorphisms of GRK5 but not GRK2 were identified from 96 subjects. The most common, GRK5 Q41L, was analyzed in cell expression systems and transgenic mice. The GRK5 Q41L locus was genotyped in 596 normal subjects and 1113 patients with heart failure. Logistic regression methods were used to determine the effect on heart failure progression, and the interaction with β-blocker therapy. Results: Compared to wild-type GRK5 Q41, the L41 variant increased β1-AR desensitization to isoproterenol in cultured cells, and accelerated desensitization of cardiac contractility while delaying resensitization in transgenic mice. The GRK5 L41 polymorphism is more common in subjects of African descent (AD); allele frequency 0.25 vs 0.013 in European descent (ED). GRK5 L41 did not increase risk of heart failure, but onset appeared delayed in AD carriers (P = 0.056). Comparing time to death or transplant (using Q41 non-β-blocker heart failure patients as the index group) β-blocker use in Q41 patients showed the typical diminished risk (adjusted odds ratio, 0.16; 95% confidence interval [CI], 0.08 to 0.34). GRK5 L41 patients had similarly diminished risk, whether treated with β-blockers (odds ratio, 0.22; 95% CI, 0.10-0.46) or not (odds ratio, 0.272; 95% CI, 0.1-0.75). Conclusions: GRK5 L41 enhances β-AR desensitization and is associated with intrinsic protection from death or transplant in heart failure patients of AD. Genotyping at this locus may be useful to identify heart failure patients who will benefit more from non-β-blockade therapies.