Estrogen Receptor Variance and CHD Risk in HERS

描述(由申请人提供)：雌激素提高高密度脂蛋白胆固醇水平--这一效果可能解释了激素替代疗法(HRT)与绝经后女性患冠心病(CHD)风险之间的有利联系。一些证据表明，遗传因素也影响高密度脂蛋白水平，尽管涉及的确切基因尚未确定。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高密度脂蛋白胆固醇的影响增加了一倍以上。具有有利基因的女性(约占女性的20%)在接受激素替代治疗时，高密度脂蛋白水平增加了26%，而在其余女性中观察到的高密度脂蛋白增加了13%。然而，这项试验规模太小，无法确定这些影响是否转化为血管造影或临床益处。心脏和雌激素替代研究(HERS)是一项大型(N=2763)HRT二级预防CHD的随机临床终点试验。这一临床试验队列提供了一个理想的机会来证实或驳斥在ERA试验中观察到的与血脂有关的关联和相互作用，并将这些观察扩展到其他雌激素敏感的中间终点和临床疾病结果。因此，我们建议根据几个ER-α基因多态对她的女性进行基因分型，并检查这些ER-α基因型别、HRT使用、高密度脂蛋白变化和CHD事件风险之间的关系。我们还将检查ER-α基因多态性对其他血脂、C反应蛋白、骨密度、静脉血栓栓塞症事件、中风、骨折和全因死亡率的影响。使用她的数据和样本是研究ER-α基因多态和雌激素作用可能调节的临床影响的有效手段。如果ER-α基因中存在常见的多态，可以改变雌激素对高密度脂蛋白以及可能其他雌激素作用领域的影响，这些信息可能会提高患者和临床医生评估HRT使用的风险和好处的能力。此外，这些信息可能导致关于雌激素作用机制、高密度脂蛋白胆固醇调节和冠心病发病机制的根本重要的新知识。

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.