Genetic variants in the alpha2C-adrenoceptor and G-protein contribute to ethnic differences in cardiovascular stress responses

Abstract

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 alpha2C-adrenergic receptor (ADRA2C del322-325) and a G-protein beta3-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 (15.8 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.

Figure 1

Figure 1a: Ethnic difference in heart rate response to cold pressor test. Boxes represent interquartile ranges, error bars the ranges for the unadjusted rise in heart rate during cold pressor testing. Black subjects had a higher unadjusted heart rate response than whites (P=0.002). Figure 1b: The interaction between the ADRA2C and GNB3 genotypes and ethnicity on heart rate response during cold pressor test. Subjects were grouped by homozygosity for the variant alleles (D/D and TT for ADRA2C and GNB3, respectively). I=Insertion, D=Deletion. Boxes represent interquartile ranges, error bars the ranges. The left panel shows the unadjusted responses for the whole group, the right panel for whites (white bars) and blacks (grey bars) separately. There were no white subjects homozygous for the ADRA2C deletion. Heart rate response differed significantly among genotype groups (P<0.001).Within genotype groups with bi-ethnic representation, there was no ethnic difference (P>0.30).

Figure 1

Figure 1a: Ethnic difference in heart rate response to cold pressor test. Boxes represent interquartile ranges, error bars the ranges for the unadjusted rise in heart rate during cold pressor testing. Black subjects had a higher unadjusted heart rate response than whites (P=0.002). Figure 1b: The interaction between the ADRA2C and GNB3 genotypes and ethnicity on heart rate response during cold pressor test. Subjects were grouped by homozygosity for the variant alleles (D/D and TT for ADRA2C and GNB3, respectively). I=Insertion, D=Deletion. Boxes represent interquartile ranges, error bars the ranges. The left panel shows the unadjusted responses for the whole group, the right panel for whites (white bars) and blacks (grey bars) separately. There were no white subjects homozygous for the ADRA2C deletion. Heart rate response differed significantly among genotype groups (P<0.001).Within genotype groups with bi-ethnic representation, there was no ethnic difference (P>0.30).

Figure 2. Effect of ethnicity on heart rate response before and after adjustment for ADRA2C del322-325 and GNB3 C825T genotypes

The upper point estimate represents the ethnic difference after adjustment for all non-genetic covariates (P=0.001), the lower point estimate represent the ethnic difference after additional adjustment for ADRA2C and GNB3 genotypes. Error bars represent 95% confidence intervals. After adjustment for genotypes, the ethnic difference was abrogated (P=0.70).