Manosroi Worapaka, Tan Jia Wei, Rariy Chevon M, Sun Bei, Goodarzi Mark O, Saxena Aditi R, Williams Jonathan S, Pojoga Luminita H, Lasky-Su Jessica, Cui Jinrui, Guo Xiuqing, Taylor Kent D, Chen Yii-Der I, Xiang Anny H, Hsueh Willa A, Raffel Leslie J, Buchanan Thomas A, Rotter Jerome I, Williams Gordon H, Seely Ellen W
Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Division of Endocrinology and Metabolism, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
J Clin Endocrinol Metab. 2017 Nov 1;102(11):4124-4135. doi: 10.1210/jc.2017-00957.
Hypertension in young women is uncommon compared with young men and older women. Estrogen appears to protect most women against hypertension, with incidence increasing after menopause. Because some premenopausal women develop hypertension, estrogen may play a different role in these women. Genetic variations in the estrogen receptor (ER) are associated with cardiovascular disease. ER-β, encoded by ESR2, is the ER predominantly expressed in vascular smooth muscle.
To determine an association of single nucleotide polymorphisms in ESR2 with salt sensitivity of blood pressure (SSBP) and estrogen status in women.
Candidate gene association study with ESR2 and SSBP conducted in normotensive and hypertensive women and men in two cohorts: International Hypertensive Pathotype (HyperPATH) (n = 584) (discovery) and Mexican American Hypertension-Insulin Resistance Study (n = 662) (validation). Single nucleotide polymorphisms in ESR1 (ER-α) were also analyzed. Analysis conducted in younger (<51 years, premenopausal, "estrogen-replete") and older women (≥51 years, postmenopausal, "estrogen-deplete"). Men were analyzed to control for aging.
Multivariate analyses of HyperPATH data between variants of ESR2 and SSBP documented that ESR2 rs10144225 minor (risk) allele carriers had a significantly positive association with SSBP driven by estrogen-replete women (β = +4.4 mm Hg per risk allele, P = 0.004). Findings were confirmed in Hypertension Insulin-Resistance Study premenopausal women. HyperPATH cohort analyses revealed risk allele carriers vs noncarriers had increased aldosterone/renin ratios. No associations were detected with ESR1.
The variation at rs10144225 in ESR2 was associated with SSBP in premenopausal women (estrogen-replete) and not in men or postmenopausal women (estrogen-deplete). Inappropriate aldosterone levels on a liberal salt diet may mediate the SSBP.
与年轻男性和老年女性相比，年轻女性患高血压的情况并不常见。雌激素似乎能保护大多数女性预防高血压，绝经后发病率会增加。由于一些绝经前女性会患高血压，雌激素在这些女性中可能发挥不同的作用。雌激素受体（ER）的基因变异与心血管疾病有关。由ESR2编码的ER-β是主要在血管平滑肌中表达的雌激素受体。
确定ESR2单核苷酸多态性与女性血压盐敏感性（SSBP）和雌激素状态之间的关联。
在两个队列的血压正常和高血压的女性及男性中进行了ESR2与SSBP的候选基因关联研究：国际高血压病理类型（HyperPATH）（n = 584）（发现队列）和墨西哥裔美国人高血压-胰岛素抵抗研究（n = 662）（验证队列）。还分析了ESR1（ER-α）的单核苷酸多态性。在较年轻（<51岁，绝经前，“雌激素充足”）和老年女性（≥51岁，绝经后，“雌激素缺乏”）中进行分析。对男性进行分析以控制年龄因素。
对HyperPATH数据中ESR2变异与SSBP进行多变量分析表明，ESR2 rs10144225次要（风险）等位基因携带者与雌激素充足的女性所导致的SSBP存在显著正相关（每个风险等位基因β = +4.4 mmHg，P = 0.004）。在高血压胰岛素抵抗研究的绝经前女性中证实了这一发现。HyperPATH队列分析显示，风险等位基因携带者与非携带者相比，醛固酮/肾素比值升高。未检测到与ESR1的关联。
ESR2中rs10144225的变异与绝经前女性（雌激素充足）的SSBP相关，而与男性或绝经后女性（雌激素缺乏）无关。高盐饮食时醛固酮水平异常可能介导了SSBP。
