GRK5 Gln41Leu polymorphism is not associated with sensitivity to β₁-adrenergic blockade in humans

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 β-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.