Estrogen Receptor Variants,HDL, and Atherosclerosis

高密度脂蛋白胆固醇水平升高与临床和解剖性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。在绝经前妇女中，雌激素相关的高密度脂蛋白升高可能解释了她们冠心病（CHD）事件发生率低的原因。最近，雌激素受体α (er - α)基因的序列变异，er - α IVS1-397 T/C，与激素替代疗法（HRT）反应中高密度脂蛋白胆固醇的两倍增加有关。然而，目前尚不清楚在绝经前雌激素暴露的情况下，这种序列变异是否也会增加HDL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生物学（PDAY）研究是一项大型横断面解剖研究，研究年龄在15至34岁之间的动脉粥样硬化程度。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DNA提取的组织，使这成为一个理想的队列，研究er - α IVS1-397基因型、HDL水平和早期动脉粥样硬化发展之间的关系。因此，我们建议在PDAY研究中测量er - α IVS1-397 T/C变异（以及其他几种er - α多态性）与女性受试者胸腹主动脉和右冠状动脉动脉粥样硬化程度之间的关系（N=700）。次要目的将包括检查er - α基因型与HDL水平之间的关系，并确定er - α基因型与疾病程度之间的关系是否可以通过HDL的基因型差异来解释。如果雌激素对高密度脂蛋白和其他因素的有利影响模式在大约20%的er - α IVS1-397 C/C基因型女性中被观察到，转化为动脉粥样硬化风险的降低，这一信息可用于显著改善雌激素用于心血管疾病一级预防的策略。

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.