GRK5 Gln41Leu Polymorphism is not Associated with Sensitivity to β ₁ -Adrenergic Blockade in Humans

Abstract

Aims A common, functionally significant polymorphism in GRK5 (Gln41Leu) encodes a gain-of-function enzyme that enhances desensitization of the β1-adrenergic receptor. GRK5 Leu41 has been postulated to confer endogenous ‘genetic β-blockade’ and contribute to an attenuated response to β-blockers in black subjects. The effects of this GRK5 variant on sensitivity to a β-blocker have not been studied in humans. We hypothesized that the GRK5 Gln41Leu variant contributes to interindividual variability in response to β-blockade and to the ethnic difference in sensitivity between black and Caucasian individuals. Materials & methods We measured the heart rate at rest and during a graded incremental exercise in 154 healthy subjects (85 white and 69 black) before and after an oral administration of 25 mg atenolol. We determined the genotypes of GRK5 (Gln41Leu), β1-adrenergic receptor (ADRB1 Ser49Gly and Arg389Gly) genotypes and plasma atenolol concentrations. The effects of genotype and covariates on sensitivity to atenolol, measured as the reduction in exercise-induced tachycardia, were determined using multiple regression analyses. Results The minor allele frequency of GRK5 Leu41 was 32.6% in blacks and 0% in whites. Black individuals were less sensitive to atenolol than white individuals (p ≤ 0.011) but this was not explained by the GRK5 genotype. The GRK5 genotype had no effect on resting heart rate before (p = 0.61) and after adjustment for age, sex, ethnicity, atenolol concentrations, BMI and ADRB1 genotypes (p = 0.81). The decrease in heart rate after atenolol administration did not differ significantly according to the GRK5 genotype at rest or after exercise, before (all p > 0.14) and after statistical adjustment for covariates (all p > 0.17). Conclusion The GRK5 Gln41Leu polymorphism does not affect sensitivity to the β1-adrenergic blocker, atenolol, during acute physiological adrenergic stimulation, nor does it contribute to the ethnic differences in sensitivity to atenolol among black and Caucasian individuals.

Genetic variation in the presynaptic norepinephrine transporter is associated with blood pressure responses to exercise in healthy humans

“…The exercise protocol was well standardized and previously described in detail [10,12,13]. On the morning (8:00–10:00 am) of the study day, subjects were admitted to a temperature-controlled room (22–23°C) in the Vanderbilt University Clinical Research Center after an overnight fast.…”

Connective Tissue Growth Factor/CCN2 Attenuatesβ-Adrenergic Receptor Responsiveness and Cardiotoxicity by Induction of G Protein–Coupled Receptor Kinase-5 in Cardiomyocytes

“…replicated in a recent study, leaving the significance of the Gln41Leu polymorphisms unsettled (Kurnik et al, 2009). …”

Atypical Actions of G Protein-Coupled Receptor Kinases

“…It is suggested that this genetic variation explains the fact that treatment with β-blockers for heart failure patients is more effective for Caucasians than for African Americans. However, another group reported that Leu41Gln polymorphism of GRK5 is not associated with sensitivity to a β-AR blockade in humans (Kurnik et al, 2009). They also showed that Leu41Gln variation does not contribute to the ethnic difference in sensitivity between African American and Caucasian populations to the β-blocker atenolol.…”