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


CONCLUSIONS
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.
Kurnik
Daniel
D
Departments of Medicine and Pharmacology, Division of Clinical Pharmacology bDepartment of Biomedical Statistics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Friedman
Eitan A
EA
Muszkat
Mordechai
M
Sofowora
Gbenga G
GG
Xie
Hong-Guang
HG
Dupont
William D
WD
Wood
Alastair J J
AJ
Stein
C Michael
CM
D000328:Adult; D044383:Black People / Q000235:genetics*; D001794:Blood Pressure / Q000502:physiology; D002319:Cardiovascular System / Q000503:physiopathology*; D002395:Catecholamines / Q000378:metabolism; D003080:Cold Temperature; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006339:Heart Rate; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D021122:Protein Subunits; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics*; D013315:Stress, Psychological / Q000235:genetics*; D044465:White People / Q000235:genetics*; D001741:Black or African American
C547774:ADRA2C protein, human; D002395:Catecholamines; C454420:G-protein beta3 subunit; D021122:Protein Subunits; D018341:Receptors, Adrenergic, alpha-2; D020962:Heterotrimeric GTP-Binding Proteins