Estrogen Receptor Variance and CHD Risk in HERS

HERS 中的雌激素受体变异和 CHD 风险

• 批准号: 6751290
• 负责人: DAVID McLeod HERRINGTON
• 金额: $ 27万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-27 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6751290
• 关键词: acute phase protein; atherosclerosis; bone density; cardiovascular disorder risk; clinical research; estrogen receptors; estrogens; female; genetic polymorphism; genetic susceptibility; genotype; high density lipoproteins; hormone therapy; human data; human therapy evaluation; human tissue; patient oriented research; protein isoforms; women' s health

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.

描述（由申请人提供）：雌激素会提高高密度脂蛋白胆固醇水平，这种效应可能解释了绝经后女性激素替代疗法（HRT）与冠心病（CHD）风险之间的有利关联。多项证据表明，遗传因素也会影响高密度脂蛋白水平，尽管所涉及的确切基因尚未确定。雌激素替代和动脉粥样硬化 (ERA) 试验 (N = 309) 的最新证据表明，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（约 20% 的女性）通过 HRT 后 HDL 增加了 26%，而其余女性则增加了 13%。然而，这项试验规模太小，无法确定这些效应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) 是一项针对 HRT 用于 CHD 二级预防的大型 (N = 2763) 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确认或反驳 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果。因此，我们建议对 HERS 女性的几种 ER-α 多态性进行基因分型，并检查这些 ER-α 基因型、HRT 使用、HDL 变化和 CHD 事件风险之间的关系。我们还将检查 ER-α 多态性对其他血浆脂质、C 反应蛋白、骨矿物质密度、静脉血栓栓塞事件、中风、骨折和全因死亡率的风险的影响。使用 HERS 的数据和样本是研究 ER-α 多态性的临床影响和雌激素作用的可能调节的有效方法。如果 ER-α 基因中存在常见的多态性，可以改变雌激素对 HDL 的影响以及雌激素作用的其他领域，则该信息可以提高患者和临床医生评估 HRT 使用风险和益处的能力。此外，这些信息可能会带来关于雌激素作用机制、HDL胆固醇调节和CHD发病机制的根本性重要新知识。