Postmenopause CHD risk: Platelet genes & hormone therapy

冠心病（CHD）是美国女性的头号杀手。激素 雌激素（E）和孕激素（P）的替代疗法（HRT）可能不再是 被认为是心脏保护的。事实上，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有益作用。 由于血小板在心肌梗死和中风的病理生理学中起着核心作用，这些发现 提出了关于HRT对冠状血管中血小板血栓形成的影响的问题。我们 已发表的和初步的数据表明：1）与男性相比，女性血小板反应性高 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ER α，4）功能性血小板多态性是CHD的风险，5） 血小板基因功能多态性与特异性抗血小板药物之间的遗传学相互作用 心血管疗法（阿司匹林、他汀类药物和GPIIb-IIla阻滞剂）。因为女性至少与男性一样易受CHD发展的遗传影响，我们假设遗传性血小板变异决定了哪些绝经后女性易受HRT的促血栓作用。我们的目标是确定女性冠心病事件的遗传预测因子。我们将对妇女健康倡议的观察性研究进行一项病例对照研究，分析1,060名经历过CHD死亡或记录的非致命性MI（病例）的妇女和2,120名未发生CHD事件的对照妇女的DNA。通过大量的CHD病例和对照，我们将检测功能性血小板多态性与CHD事件之间的相关性（目的1）以及这些多态性与HRT之间的相互作用（目的2）。我们已经组建了一个优秀的研究小组，并拥有极其宝贵的资源，使我们处于一个独特的位置，以实现这些目标和我们的长期目标，优化妇女冠心病的预防和管理。

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.