Interacting effects of gender and genotype on blood pressure response to hydrochlorothiazide

Genetic factors may influence blood pressure (BP) response to diuretic therapy through their effects on activity of the renin-angiotensin-aldosterone system (RAAS). The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene is associated with variation in serum ACE activity and may influence BP in a gender-specific manner.

We measured the I/D polymorphism in 206 non-Hispanic women (130 blacks, 76 whites) and 170 non-Hispanic men (62 blacks, 108 whites) with essential hypertension (age 48 +/- 7 years, mean +/- SD) who underwent monotherapy with hydrochlorothiazide (HCTZ) 25 mg daily for four weeks.

In both genders, serum ACE activity increased in a co-dominant fashion in association with the D-allele (P < 0.001 for both genders). In regression models that considered the effects of baseline BP, race, gender, age, waist-to-hip ratio, and measures of the RAAS, there was significant interaction between the effects of the ACE genotype and gender on the responses of both systolic and diastolic BP to HCTZ (for systolic BP response, P = 0.03; for diastolic BP response, P = 0.001). Among women, mean declines in systolic and diastolic BP were greater in II than in DD homozygotes; whereas among men, mean declines in systolic and diastolic BP were greater in DD than in II homozygotes. In models that included the effects of race, gender, age, and waist-to-hip ratio, there was also significant interaction between the effects of the ACE genotype and gender on pre-treatment urinary aldosterone excretion (P = 0.01) and change in urinary aldosterone excretion in response to HCTZ (P = 0.007). The genotypes that were associated with the greatest BP responses to HCTZ (II homozygotes in women and DD homozygotes in men) had the lowest pre-treatment urinary aldosterone excretion and the greatest increase in urinary aldosterone excretion in response to HCTZ.

The relationship between the ACE I/D polymorphism and antihypertensive response to a standard dose of HCTZ differs significantly between women and men. Because the D-allele was associated with significant, co-dominant increases in serum ACE activity in both genders, the gender-specific effects of the I/D polymorphism on BP response to HCTZ may be mediated subsequent to the enzymatic generation of angiotensin II.