Antihypertensive Pharmacogenetics: The C825T Polymorphism of G-Protein β3 Subunit (GNB3) Is Associated with Greater Blood Pressure (BP) Response to Diuretic Therapy in Essential Hypertension (EHT)
Knowledge of genetic factors that influence pharmacodynamics of responses to antihypertensive drugs may provide insights into molecular mechanisms contributing to elevation of BP and response to treatment. The T-allele of the C825T polymorphism of the gene coding for the G-protein β3 subunit (GNB3) has been associated with increased Na+-H+ exchange and low plasma renin in individuals with EHT. Moreover, diminished counterregulatory activity of the renin-angiotensin system has been associated with greater BP declines in response to negative sodium balance induced by diuretic therapy. To assess the possible influence of GNB3 genotype on BP response to diuretic therapy, we measured the C825T polymorphism in community-based samples of 204 blacks (139 women, 65 men) and 192 whites (77 women, 115 men) with EHT (mean age=48±7 years) who underwent monotherapy with hydrochlorothiazide (HCTZ) for 4 weeks. In univariate analyses, the TT genotype was significantly associated with lower plasma renin activity (p<0.001) and higher plasma aldosterone concentration (p<0.019). In addition, mean declines in systolic blood pressure (SBP) and diastolic blood pressure (DBP) were 6±2 mmHg (p<0.001) and 5±1 mmHg (p<0.001) greater, respectively, in TT than in CC homozygotes. Responses in heterozygotes were intermediate between homozygote groups. Other univariate predictors of greater declines in both SBP and DBP were higher pretreatment BP (p<0.001), black race (p<0.001), female gender (p<0.005), older age (p≤0.064), lower waist/hip ratio (p≤0.087), and lower plasma renin activity (p<0.001). Even after considering effects of these other predictors, the TT genotype remained associated with greater declines in SBP (p<0.058) and DBP (p<0.001). Thus, the C825T polymorphism of GNB3 may help identify individuals with EHT who are more responsive to diuretic therapy and may have Na+-dependent BP elevation.