Estrogen Receptor Variants,HDL, and Atherosclerosis

雌激素受体变异体、HDL 和动脉粥样硬化

• 批准号: 6865628
• 负责人: DAVID McLeod HERRINGTON
• 金额: $ 27.17万
• 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 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6865628
• 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.

HDL胆固醇水平的升高与临床和解剖动脉粥样硬化率较低有关，即使在青少年和年轻人中也是如此。在绝经前妇女中，HDL与雌激素相关的增加可能是其冠心病（CHD）事件的低率。最近，雌激素受体-Alpha（ER-Alpha）基因的序列变体ER-Alpha IVS1-397 T/C）与激素替代治疗（HRT）响应于激素胆固醇（HRT）的HDL胆固醇的两倍增加有关。但是，尚不清楚该序列变体是否在月经前雌激素暴露以及这种差异转化为动脉粥样硬化风险的降低中是否会增加HDL水平。 青少年动脉粥样硬化（PDAY）研究的病理生物学是一项大型横断面尸检研究，对15至34岁的受试者的动脉粥样硬化程度。动脉粥样硬化病变的详细描述，再加上心血管危险因素的数据以及可用于DNA提取的组织的数据，使这是一个理想的同类群，可以在其中检查ER-Alpha IVS1-397绅士型，HDL水平，HDL水平和早期动脉粥样硬化的发展之间的关联。因此，我们建议测量胸腔和腹主动脉和腹主动脉中动脉粥样硬化的er-alpha IVS1-397 T/C变体（以及其他几种ER-Alpha多态性）与PDAY研究中女性受试者的右冠状动脉之间的关联（N = 700）。次要目的将包括检查ER-Alpha基因型与HDL水平之间的关联，并确定是否可以通过HDL的基因型差异来解释ER-Alpha基因型与疾病程度之间的关联。 如果估计有20％的ER-Al-Alpha IVS1-397 C/C基因型的雌激素影响对HDL的有利模式以及其他因素的其他因素，可以转化为降低动脉粥样硬化的风险，则该信息可用于大幅改善雌激素用于雌激素用于雌激素用于雌激素用于雌激素的策略。