Estrogen Receptor Variants, HDL, & Atherosclerosis

雌激素受体变体，HDL，

• 批准号: 6730159
• 负责人: DAVID McLeod HERRINGTON
• 金额: $ 53.4万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6730159
• 关键词: African American; adolescence (12-20); aorta; atherosclerosis; cardiovascular disorder prevention; caucasian American; clinical research; coronary artery; disease /disorder onset; estrogen receptors; female; gene expression; genetic polymorphism; genotype; high density lipoproteins; hormone therapy; human data; human genetic material tag; pathologic process; polymerase chain reaction; postmortem; racial /ethnic difference; thorax; women' s health; young adult human (21-34)

Increased levels of HDL cholesterol are associated with lower rates of clinical and anatomic atherosclerosis, even in adolescents and young adults. In premenopausal women, estrogen-associated increases in HDL may account for their low rates of coronary heart disease (CHD) events. Recently, a sequence variant in the estrogen receptor-alpha (ER-alpha) gene, ER-alpha IVS1-397 T/C), has been linked to twofold greater increases in HDL cholesterol in response to hormone replacement therapy (HRT). However, it remains unclear whether this sequence variant also augments HDL levels in the setting of premenopausal estrogen exposure and whether such differences translate into greater reductions in atherosclerosis risk. The Pathobiology of Atherosclerosis in Youth (PDAY) study is a large cross-sectional autopsy study of the extent of atherosclerosis in subjects aged 15 to 34 years. The detailed descriptions of atherosclerotic lesions, combined with data on cardiovascular risk factors and access to tissue for DNA extraction, makes this an ideal cohort in which to examine the association between ER-alpha IVS1-397 gentotypes, HDL levels, and development of early atherosclerosis. Therefore we propose to measure the association between the ER-alpha IVS1-397 T/C variant (and several other ER-alpha polymorphisms) and extent of atherosclerosis in the thoracic and abdominal aorta and the right coronary artery in female subjects in the PDAY study (N=700). Secondary aims will include examination of the association between the ER-alpha genotypes and HDL levels, and a determination of whether an association between ER-alpha genotype and extent of disease can be accounted for by genotypic differences in HDL. If the favorable pattern of estrogen effects on HDL and other factors seen in the estimated 20% of women with the ER-alpha IVS1-397 C/C genotype translates into a reduction in risk for atherosclerosis, this information could be used to dramatically improve strategies for use of estrogen for primary prevention of cardiovascular disease.

高密度脂蛋白胆固醇水平升高与临床和解剖动脉粥样硬化发生率降低有关，即使在青少年和年轻人中也是如此。在绝经前女性中，雌激素相关的高密度脂蛋白升高可能是她们冠心病 (CHD) 事件发生率较低的原因。最近，雌激素受体-α (ER-α) 基因（ER-α IVS1-397 T/C）中的一个序列变异与激素替代疗法 (HRT) 引起的 HDL 胆固醇增加两倍有关。然而，目前尚不清楚这种序列变异是否也会在绝经前雌激素暴露的情况下增加高密度脂蛋白水平，以及这种差异是否会转化为动脉粥样硬化风险的更大降低。 青年动脉粥样硬化病理学 (PDAY) 研究是一项针对 15 至 34 岁受试者动脉粥样硬化程度的大型横断面尸检研究。对动脉粥样硬化病变的详细描述，结合心血管危险因素的数据和获取组织进行 DNA 提取的数据，使其成为检查 ER-α IVS1-397 基因型、HDL 水平和早期动脉粥样硬化发展之间关系的理想队列。因此，我们建议在 PDAY 研究 (N=700) 中测量 ER-α IVS1-397 T/C 变异（以及其他几种 ER-α 多态性）与女性受试者胸主动脉、腹主动脉和右冠状动脉动脉粥样硬化程度之间的关联。次要目标包括检查 ER-α 基因型与 HDL 水平之间的关联，并确定 ER-α 基因型与疾病程度之间的关联是否可以通过 HDL 基因型差异来解释。 如果在估计 20% 具有 ER-alpha IVS1-397 C/C 基因型的女性中观察到雌激素对 HDL 和其他因素的有利影响模式转化为动脉粥样硬化风险的降低，那么该信息可用于显着改进使用雌激素进行心血管疾病一级预防的策略。