Antihypertensive Pharmacogenetics: Effects of Angiotensin-Converting-Enzyme (ACE) Genotype-By-Gender Interaction on Blood Pressure (BP) Responses to a Thiazide Diuretic in Essential Hypertension (EHT)
Previous studies suggest that genetic factors influence the BP response to changes in Na+ balance by altering activity of the renin-angiotensin system. The insertion/deletion (I/D) polymorphism of the ACE gene is known to be associated with variation in plasma ACE activity and may influence BP in a gender-specific manner. To assess effects of the ACE genotype and gender on BP responses to diuretic therapy, we measured the I/D polymorphism in community-based samples of 197 Blacks (133 women, 64 men) and 187 Whites (77 women, 110 men) with EHT (mean age= 48±7 years), who underwent monotherapy with hydrochlorothiazide (HCTZ) for 4 weeks. Consistent with other studies, the D-allele was associated with significant codominant increases in plasma ACE activity in all race-gender groups. Univariate predictors of greater declines in both systolic BP (SBP) and diastolic BP (DBP) were higher pretreatment BP (P <0.001), Black race (P ≤0.005), female gender (P <0.001), older age (P ≤0.064), and lower waist/hip ratio (P ≤0.087). In linear models that considered the effects of all predictors, there was significant interaction between the effects of ACE genotype and gender on the responses of both SBP (P ≤0.004) and DBP (P <0.001) to HCTZ. Among women of both races, mean declines in SBP (P ≤0.012) and DBP (P ≤0.025) were greater in II than in DD homozygotes. In contrast, among men of both races mean declines in SBP (P ≤0.164) and DBP (P ≤0.007) were greater in DD than in II homozygotes. In both genders, BP declines were intermediate in heterozygotes. Thus, although the effects of ACE genotype on plasma ACE activity are independent of gender, the effects of ACE genotype on BP responses to thiazide diuretic therapy appear to be gender-specific.