Psaty Bruce M, Smith Nicholas L, Heckbert Susan R, Vos Hans L, Lemaitre Rozenn N, Reiner Alexander P, Siscovick David S, Bis Joshua, Lumley Thomas, Longstreth W T, Rosendaal Frits R
Cardiovascular Health Research Unit, 1730 Minor Ave, Suite 1360, Seattle, WA 98101, USA.
JAMA. 2002 Apr 3;287(13):1680-9. doi: 10.1001/jama.287.13.1680.
A genetic variant in alpha-adducin has been associated with renal sodium reabsorption and salt-sensitive hypertension. Whether this genetic variant modifies the effect of diuretic therapy on the incidence of myocardial infarction (MI) and stroke is unknown.
To estimate the interaction between alpha-adducin and diuretic therapy on the risk of MI or stroke. Specifically, we hypothesized that in participants with treated hypertension, the risk of MI or stroke associated with diuretic use would be lower in carriers of the adducin variant than in carriers of the adducin wild-type genotype.
DESIGN, SETTING, AND PARTICIPANTS: Population-based case-control study of patients enrolled in a health maintenance organization, treated pharmacologically for hypertension, and genotyped as homozygous carriers of the adducin wild-type genotype or carriers of 1 or 2 copies of the Trp460 variant allele. Cases had a first nonfatal MI (n = 206) or stroke (n = 117) between January 1995 and December 1998. Controls (n = 715) were a stratified random sample of pharmacologically treated hypertensive patients who were matched to MI cases by age, sex, and calendar year.
Risk of the combined outcome of first nonfatal MI or stroke.
The adducin variant was present in more than one third of the participants. Among the 653 carriers of the adducin wild-type genotype, diuretic therapy was not associated with the risk of MI or stroke (odds ratio [OR], 1.09; 95% confidence interval [CI], 0.78-1.52). Among the 385 carriers of the adducin variant allele, diuretic therapy was associated with a lower risk of the combined outcome of MI and stroke than other antihypertensive therapies (OR, 0.49; 95% CI, 0.32-0.77). The OR in carriers of the adducin variant was less than half of the OR in carriers of the wild-type genotype (P =.005). The case-control synergy index (SI) was 0.45 (95% CI, 0.26-0.79) for the combined outcome of MI and stroke. The point estimates of the diuretic-adducin interaction were similar in separate analyses of MI (SI, 0.41; 95% CI, 0.21-0.80) and stroke (SI, 0.53; 95% CI, 0.24-1.19). The diuretic-adducin interaction was not confounded by traditional cardiovascular risk factors, was specific to diuretic therapy but not present for other major antihypertensive drug classes, and did not differ substantially between subgroups defined by age, sex, race, diabetes, and history of cardiovascular disease.
In carriers of the adducin variant, diuretic therapy was associated with a lower risk of combined MI or stroke than other antihypertensive therapies. If these findings are confirmed in other studies, this large subgroup of the hypertensive population may be especially likely to benefit from low-dose diuretic therapy.
α-内收蛋白的一种基因变异与肾钠重吸收及盐敏感性高血压相关。该基因变异是否会改变利尿剂治疗对心肌梗死（MI）和中风发生率的影响尚不清楚。
评估α-内收蛋白与利尿剂治疗在MI或中风风险上的相互作用。具体而言，我们假设在接受高血压治疗的参与者中，携带内收蛋白变异的个体使用利尿剂时发生MI或中风的风险低于携带内收蛋白野生型基因型的个体。
设计、地点和参与者：基于人群的病例对照研究，研究对象为参加健康维护组织、接受高血压药物治疗且基因分型为内收蛋白野生型基因型纯合携带者或携带1个或2个Trp460变异等位基因的患者。病例为1995年1月至1998年12月期间首次发生非致命性MI（n = 206）或中风（n = 117）的患者。对照（n = 715）是经药物治疗的高血压患者的分层随机样本，按年龄、性别和日历年与MI病例匹配。
首次非致命性MI或中风的联合结局风险。
超过三分之一的参与者存在内收蛋白变异。在内收蛋白野生型基因型的653名携带者中，利尿剂治疗与MI或中风风险无关（优势比[OR]，1.09；95%置信区间[CI]，0.78 - 1.52）。在内收蛋白变异等位基因的385名携带者中，与其他抗高血压治疗相比，利尿剂治疗与MI和中风联合结局的风险较低（OR，0.49；95% CI，0.32 - 0.77）。内收蛋白变异携带者的OR不到野生型基因型携带者OR的一半（P = 0.005）。MI和中风联合结局的病例对照协同指数（SI）为0.45（95% CI，0.26 - 0.79）。在MI（SI，0.41；95% CI，0.21 - 0.80）和中风（SI，0.53；95% CI，0.24 - 1.19）的单独分析中，利尿剂 - 内收蛋白相互作用的点估计值相似。利尿剂 - 内收蛋白相互作用不受传统心血管危险因素的混杂，特定于利尿剂治疗，其他主要抗高血压药物类别不存在这种相互作用，并且在按年龄、性别、种族、糖尿病和心血管疾病史定义的亚组之间没有实质性差异。
在内收蛋白变异携带者中，与其他抗高血压治疗相比，利尿剂治疗与MI或中风联合风险较低相关。如果这些发现在其他研究中得到证实，这一高血压人群的大亚组可能特别有可能从低剂量利尿剂治疗中获益。
