Schwartz Gary L, Turner Stephen T, Chapman Arlene B, Boerwinkle Eric
Division of Hypertension, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Kidney Int. 2002 Nov;62(5):1718-23. doi: 10.1046/j.1523-1755.2002.00624.x.
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.
遗传因素可能通过影响肾素 - 血管紧张素 - 醛固酮系统（RAAS）的活性来影响血压（BP）对利尿剂治疗的反应。血管紧张素转换酶（ACE）基因的插入/缺失（I/D）多态性与血清ACE活性的变化相关，并且可能以性别特异性方式影响血压。
我们测量了206名非西班牙裔女性（130名黑人，76名白人）和170名非西班牙裔男性（62名黑人，108名白人）原发性高血压患者（年龄48±7岁，均值±标准差）的I/D多态性，这些患者接受每日25 mg氢氯噻嗪（HCTZ）单药治疗四周。
在两性中，血清ACE活性与D等位基因呈共显性增加（两性均P < 0.001）。在考虑基线血压、种族、性别、年龄、腰臀比和RAAS指标影响的回归模型中，ACE基因型和性别对收缩压和舒张压对HCTZ反应的影响之间存在显著交互作用（对于收缩压反应，P = 0.03；对于舒张压反应，P = 0.001）。在女性中，II型纯合子的收缩压和舒张压平均下降幅度大于DD型纯合子；而在男性中，DD型纯合子的收缩压和舒张压平均下降幅度大于II型纯合子。在包括种族、性别、年龄和腰臀比影响的模型中，ACE基因型和性别对治疗前尿醛固酮排泄（P = 0.01）和HCTZ治疗后尿醛固酮排泄变化（P = 0.007）的影响之间也存在显著交互作用。与HCTZ血压反应最大相关的基因型（女性中的II型纯合子和男性中的DD型纯合子）治疗前尿醛固酮排泄最低，HCTZ治疗后尿醛固酮排泄增加最大。
ACE I/D多态性与标准剂量HCTZ降压反应之间的关系在女性和男性之间存在显著差异。由于D等位基因与两性血清ACE活性显著的共显性增加相关，I/D多态性对HCTZ血压反应的性别特异性影响可能在血管紧张素II酶促生成之后介导。
