Estrogen Receptor Variance and CHD Risk in HERS

描述（由申请人提供）：雌激素升高HDL胆固醇水平-这一效应可能是绝经后妇女激素替代疗法（HRT）与冠心病（CHD）风险之间有利相关的原因。一些证据表明，遗传因素也影响HDL水平，尽管涉及的精确基因尚未确定。最近来自雌激素替代和动脉粥样硬化（ERA）试验（N = 309）的证据表明，雌激素受体α（ER-α）基因中的某些等位基因变异与雌激素对HDL胆固醇的影响增加两倍以上有关。具有有利基因型的女性（CA。20%的妇女）经历了26%的HDL增加与HRT相比，在其余妇女中观察到13%的增加。然而，这项试验规模太小，无法确定这些效果是否转化为血管造影或临床获益。心脏和雌激素替代研究（HERS）是一项大型（N = 2763）HRT用于CHD二级预防的随机临床终点试验。该临床试验队列提供了一个理想的机会来证实或反驳ERA试验中观察到的与血脂相关的关联和相互作用，并将这些观察结果扩展到其他雌激素敏感的中间终点和临床疾病结局。因此，我们建议对HERS妇女进行ER-α基因多态性的基因分型，并研究这些ER-α基因型、HRT使用、HDL变化和CHD事件风险之间的关系。我们还将研究ER-α多态性对其他血脂、C-反应蛋白、骨密度、静脉血栓栓塞事件风险、中风、骨折和全因死亡率的影响。使用来自HERS的数据和标本是研究ER-α多态性的临床影响和雌激素作用的可能调节的有效手段。如果ER-α基因中存在共同的多态性，可以改变雌激素对HDL的影响，并可能改变雌激素作用的其他领域，那么这些信息可以提高患者和临床医生评估HRT使用的风险和益处的能力。此外，这一信息可能会导致从根本上重要的新知识的机制，雌激素的作用，高密度脂蛋白胆固醇的调节，冠心病的发病机制。

DESCRIPTION (provided by applicant): Estrogen raises HDL cholesterol levels - an effect that may account for the favorable association between hormone replacement therapy (HRT) and coronary heart disease (CHD) risk in postmenopausal women. Several lines of evidence suggest that genetic factors also influence HDL levels, although the precise genes involved have not yet been determined. Recent evidence from the Estrogen Replacement and Atherosclerosis (ERA) trial (N = 309) indicates that certain allelic variants in the estrogen receptor-alpha (ER-alpha) gene are associated with more than a twofold increase in estrogen's effects on HDL cholesterol. Women with the favorable genotype (ca. 20% of women) experienced a 26% increase in HDL with HRT compared with a 13% increase observed in the remaining women. However, this trial was too small to determine if these effects translate into an angiographic or clinical benefit. The Heart and Estrogen Replacement Study (HERS) was a large (N = 2763) randomized clinical endpoint trial of HRT for secondary prevention of CHD. This clinical trial cohort provides an ideal opportunity to confirm or refute the associations and interactions observed in the ERA trial with respect to lipids, and extend these observations to other estrogen-sensitive intermediate endpoints and clinical disease outcomes. Therefore, we propose to genotype HERS women with respect to several ER-alpha polymorphisms, and to examine the relationship between these ER-alpha genotypes, HRT use, change in HDL, and risk for CHD events. We will also examine the effects of ER-alpha polymorphisms on other plasma lipids, C-reactive protein, bone mineral density, risk for venous thromboembolic events, stroke, fractures, and all-cause mortality. Use of data and specimens from HERS is an efficient means to study the clinical impact of ER-alpha polymorphisms and possible modulation of estrogen action. If there are common polymorphisms in the ER-alpha gene that modify estrogen's effects on HDL and possibly other domains of estrogen action, this information could improve patients' and clinicians' ability to assess risks and benefits of HRT use. In addition, this information could lead to fundamentally important new knowledge about mechanisms of estrogen action, regulation of HDL cholesterol, and pathogenesis of CHD.