Postmenopause CHD risk: Platelet genes & hormone therapy

冠心病(CHD)是美国女性的头号杀手。荷尔蒙 雌激素(E)和孕酮(P)的替代疗法(HRT)可能不再是 被认为对心脏有保护作用。事实上，来自HERS和WHI研究的数据表明，E+P可能 增加心肌梗塞(MI)和中风，尽管它对胆固醇水平有好处。 由于血小板在心肌梗塞和中风的病理生理学中起着核心作用，这些发现 提出关于HRT对冠状动脉中血小板血栓形成的影响的问题。我们的 已公布的初步数据显示，1)与男性相比，女性的血小板具有高反应性 血小板，2)性激素增强血小板反应性，3)血小板表达雌激素受体(ER)β和ERα，4)功能性血小板多态是冠心病的危险因素，5)有 血小板基因功能多态与特异性基因的药物遗传学相互作用 心血管治疗(阿司匹林、他汀类药物和GPIIb-ILLA阻滞剂)。由于女性至少和男性一样容易受到遗传因素对冠心病发展的影响，我们假设遗传的血小板变异决定了哪些绝经后女性容易受到HRT的血栓前效应的影响。我们在这项提案中的目标是确定女性冠心病事件的遗传预测因素。我们将对女性健康倡议的观察性研究进行一项病例对照研究，分析1060名经历过冠心病死亡或有记录的非致命性心肌梗死(病例)的女性的DNA，以及2120名没有冠心病事件的对照组的DNA。对于如此多的CHD病例和对照，我们将测试功能性血小板多态与CHD事件之间的关联(目标1)，以及这些多态与作为CHD事件风险的HRT之间的相互作用(目标2)。我们组建了一支优秀的研究团队，拥有极其宝贵的资源，这使我们处于独特的地位，能够实现这些目标和我们优化女性冠心病预防和管理的长期目标。

Coronary heart disease (CHD) is the number one killer of women in the United States. Hormone replacement therapy (HRT) with estrogen (E) and progesterone (P) should probably no longer be considered cardioprotective. In fact, data from the HERS and WHI studies indicate E+P may increase myocardial infarction (MI) and stroke despite its beneficial effects on cholesterol levels. Since blood platelets play a central role in the pathophysiology of MI and stroke, these findings raise questions about the effect of HRT on platelet thrombus formation in coronary vessels. Our published and preliminary data show that 1) female platelets are hyperreactive compared to male platelets, 2) sex hormones enhance platelet reactivity, 3) platelets express estrogen receptor (ER) beta and ER alpha, 4) functional platelet polymorphisms are risks for CHD, and 5) there are pharmacogenetic interactions between functional polymorphisms of platelet genes and specific cardiovascular therapies (aspirin, statins, and GPIIb-Illa blockers). Because women are at least as predisposed as men to genetic influences on CHD development, we hypothesize that inherited platelet variants dictate which postmenopausal women are susceptible to the prothrombotic effects of HRT. Our goal in this proposal is to identify genetic predictors of CHD events in women. We will perform a case-control study on the Observational Study of the Women's Health Initiative, analyzing DNA from 1,060 women who have experienced a CHD death or documented nonfatal MI (cases) and from 2,120 controls not having a CHD event. With this large number of CHD cases and controls we will test for associations between functional platelet polymorphisms and CHD events (Aim 1) and interactions between these polymorphisms and HRT as a risk for CHD events (Aim 2). We have assembled an excellent group of investigators and have an extremely valuable resource, putting us in a unique position to achieve these goals and our long-term goal of optimizing the prevention and management of CHD in women.