Genetic variants in the α2C-adrenoceptor and G-protein contribute to ethnic differences in cardiovascular stress responses

Objectives Cardiovascular responses to stressors are regulated by sympathetic activity, increased in black Americans, and associated with future cardiovascular morbidity. Our aim was to determine whether two functional variants in genes regulating sympathetic activity, a deletion in the alpha(2C)-adrenergic receptor (ADRA2C del322-325) and a G-protein beta 3-subunit variant (GNB3 G825T), affect cardiovascular responses to physiologic stressors and contribute to their ethnic differences. Methods We measured heart rate and blood pressure responses to a cold pressor test (CPT) in 79 healthy participants (40 blacks, 39 whites), aged 25.7 +/- 5.3 years, and determined genotypes for the ADRA2C and GNB3 variants. We examined the response variables (increase in heart rate and blood pressure) in multiple linear regression analyses adjusting first for baseline measures, ethnicity, and other covariates, and then additionally for genotypes. Results Black participants had a greater heart rate response to CPT than whites [mean difference, 9.9 bpm; 95% confidence interval (CI), 4.1 to 15.6; P=0.001]. Both the ADRA2C del/del (115.8 bpm; 95% CI, 8.0-23.7; P<0.001) and GNB3 T/T genotypes (6.8 bpm; 95% CI, 0.9-12.7; P=0.026) were associated with greater heart rate response. After adjusting for genotypes, the ethnic difference was abrogated (1.3 bpm; 95% CI, -5.4-8.0; P=0.70), suggesting that the genetic variants contributed substantially to ethnic differences. Conclusion Variation in genes that regulate sympathetic activity affects hemodynamic stress responses and contributes to their ethnic differences. This study elucidates how genetic factors may in part explain ethnic differences in cardiovascular regulation.