GRK5 Gln41Leu polymorphism is not associated with sensitivity to beta(1)-adrenergic blockade in humans.
OBJECTIVE
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.


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).


CONCLUSIONS
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.
Kurnik
Daniel
D
Vanderbilt University, Nashville, TN, USA.
Cunningham
Andrew J
AJ
Sofowora
Gbenga G
GG
Kohli
Utkarsh
U
Li
Chun
C
Friedman
Eitan A
EA
Muszkat
Mordechai
M
Menon
Usha B
UB
Wood
Alastair Jj
AJ
Stein
C Michael
CM
D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000328:Adult; D000483:Alleles; D001262:Atenolol / Q000494:pharmacology; D044383:Black People; D004562:Electrocardiography; D005260:Female; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000235:genetics*; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D010597:Pharmacogenetics / Q000379:methods; D011110:Polymorphism, Genetic / Q000235:genetics*; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics*; D013610:Tachycardia / Q000208:ethnology / Q000235:genetics; D044465:White People
D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D018342:Receptors, Adrenergic, beta-1; D001262:Atenolol; D054774:G-Protein-Coupled Receptor Kinase 5; C517898:GRK5 protein, human