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.

高密度脂蛋白胆固醇水平的升高与临床和解剖动脉粥样硬化率的降低有关，即使在青少年和年轻人中也是如此。在绝经前的女性中，雌激素相关的高密度脂蛋白的增加可能是她们冠心病(CHD)事件发生率较低的原因。最近，雌激素受体-α(ER-α)基因的一个序列变异，ER-αIVS1-397T/C)被认为与激素替代治疗(HRT)导致的高密度脂蛋白胆固醇增加两倍有关。然而，目前尚不清楚该序列变体是否也增加了绝经前雌激素暴露的高密度脂蛋白水平，以及这种差异是否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，结合关于心血管危险因素和获取组织进行DNA提取的数据，使这是一个理想的队列，用于检查ER-αIVS1-397正确型、高密度脂蛋白水平和早期动脉粥样硬化的发展之间的关联。因此，我们建议在PDAY研究中测量ER-αIVS1-397T/C变异(和其他几个ER-α多态)与女性受试者胸主动脉、腹主动脉和右冠状动脉粥样硬化程度的相关性(N=700)。次要目标将包括检查ER-α基因类型和高密度脂蛋白水平之间的关联，以及确定ER-α基因类型和疾病程度之间的关联是否可以通过高密度脂蛋白的基因差异来解释。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-αIVS1-397C/C基因女性中看到，转化为动脉粥样硬化风险的降低，这一信息可以被用来显著改进使用雌激素作为心血管疾病一级预防的策略。