Beta-1-adrenoceptor genetic variants and ethnicity independently affect response to beta-blockade

Objectives Black patients may be less responsive to β-blockers than whites. Genetic variants in the β₁-adrenergic receptor (β₁-AR) associated with lesser response to β-blockers are more common in blacks than in whites. The purpose of this study was to determine whether ethnic differences in response to β-blockade can be explained by differing distributions of functional genetic variants in the β₁-AR. Methods We measured sensitivity to β-blockade by the attenuation of exercise-induced tachycardia in 165 patients (92 whites), who performed a graded bicycle exercise test before and 2.5 h after oral atenolol (25 mg). We determined heart rate at rest and at three exercise levels from continuous ECG recordings and calculated the area under the curve. We also measured plasma atenolol concentrations and determined genotypes for variants of the β₁-AR (Ser49Gly, Arg389Gly) and α_2C-AR (del322-325). The effects of ethnicity, genotype, and other covariates on the heart rate reduction after atenolol were estimated in multiple regression analyses. Results Atenolol resulted in a greater reduction in exercise heart rate in whites than in blacks (P=0.006). β₁-AR Arg389 (P=0.003), but not the α_2C-AR 322-325 insertion allele (P=0.31), was independently associated with a greater reduction in heart rate area under the curve. Ethnic differences in sensitivity to atenolol remained significant (P=0.006) after adjustment for β₁-AR and α_2C-AR genotypes. Conclusion Ethnic differences in sensitivity to the β₁-blocker atenolol persist even after accounting for different distributions of functional genetic β₁-AR variants, suggesting that additional, as yet unidentified factors contribute to such ethnic differences.