Key result
The GRK5 Gln41Leu polymorphism did not significantly affect the atenolol-induced decrease in heart rate at rest or after exercise (all p > 0.17 after statistical adjustment).
Why the study?
Does the GRK5 Gln41Leu polymorphism attenuate sensitivity to the beta1-blocker atenolol in healthy individuals?
Observational (n=154)
No
Does the GRK5 Gln41Leu polymorphism attenuate sensitivity to the beta1-blocker atenolol in healthy individuals?
p-value: p=>0.17
This pharmacogenetic study demonstrates that the GRK5 Gln41Leu polymorphism does not account for the observed ethnic differences in acute sensitivity to beta-blockade between Black and White individuals.
GRK5 Gln41Leu testing should not guide atenolol dosing in healthy individuals; leaves open other contributors to ethnic differences in beta-blocker sensitivity.
AIMS: A common, functionally significant polymorphism in GRK5 (Gln41Leu) encodes a gain-of-function enzyme that enhances desensitization of the beta(1)-adrenergic receptor. GRK5 Leu41 has been postulated to confer endogenous 'genetic beta-blockade' and contribute to an attenuated response to beta-blockers in black subjects. The effects of this GRK5 variant on sensitivity to a beta-blocker have not been studied in humans. We hypothesized that the GRK5 Gln41Leu variant contributes to interindividual variability in response to beta-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), beta(1)-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 < or = 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 beta(1)-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.
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Kurnik et al. (2009) conducted an observational in Healthy subjects (n=154). GRK5 Gln41Leu polymorphism vs. GRK5 Gln41 homozygotes (wild-type) was evaluated on Sensitivity to atenolol (reduction in exercise-induced tachycardia at rest and at maximal exercise) (p=>0.17). The GRK5 Gln41Leu polymorphism did not significantly affect the atenolol-induced decrease in heart rate at rest or after exercise (all p > 0.17 after statistical adjustment).
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