Genetic Variants Associated with CVD Risk and Hormone Therapy Interactions

描述（由申请人提供）：心血管疾病（CVD）是美国死亡和残疾的主要原因。一个人的心血管疾病风险包含大量的遗传成分。沿着高遗传性，血脂浓度也是心血管疾病风险的重要决定因素。最近，已经有几个大的，协同努力，调查血脂水平和心血管疾病的遗传学在人口为基础的研究。无论这些研究多么成功，大约70%的血脂水平遗传变异仍然无法解释。一个流行的假设指出，在以前的研究中未检测的罕见遗传变异可能占这种无法解释的变异的很大一部分。性类固醇激素及其受体也是血脂水平和CVD风险的关键决定因素。一个重要的未解决的问题是遗传变异性是否影响雌激素和/或孕激素在改变血脂水平和心血管疾病风险方面的作用。我们将使用遗传数据、健康史、脂质浓度和来自妇女健康倡议（WHI）的关于绝经治疗（HT）的随机临床试验的数据来：（1）鉴定与欧洲美洲（EA）和非洲美洲（AA）绝经后妇女的血浆脂质水平相关的罕见遗传变异;和（2）鉴定与HT相互作用以改变EA和AA绝经后妇女的血脂水平和CVD风险的罕见遗传变异。从这项研究中产生的信息将是至关重要的，在确定遗传变异对妇女健康的影响，并优先考虑他们的干预研究，旨在最大限度地提高HT的整体临床效益，并尽量减少其相关的心血管风险。研究结果还可能为疾病途径和机制提供有价值的见解，并为绝经后女性血脂异常和CVD的筛查，预防和治疗确定新的靶点。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is a major cause of death and disability in the United States. An individual's risk for CVD contains a substantial genetic component. Along with being highly heritable, plasma lipid concentrations are also strong determinants of CVD risk. Recently, there have been several large, concerted efforts to investigate the genetics of plasma lipid levels and CVD in population based studies. However successful these studies have been, approximately 70% of the genetic variance in plasma lipid levels remains unexplained. A popular hypothesis states that rare genetic variants that were un-assayed in previous studies may account for a significant portion of this unexplained variation. Sex steroid hormones and their receptors are also critical determinants of plasma lipid levels and CVD risk. An important unresolved question is whether genetic variability influences the effect of estrogen and/or progesterone in modifying lipid levels and risk for CVD. We will use genetic data, health histories, lipid concentrations, and data from a randomized clinical trial on hormone-therapy (HT) from the Women's Health Initiative (WHI) to: (1) identify rare genetic variants associated with plasma lipid levels in European America (EA) and African American (AA) postmenopausal women; and (2) identify rare genetic variants that interact with HT to modify plasma lipid levels and risk for CVD in EA and AA postmenopausal women. Information generated from this study will be critical in determining the impact of genetic variants on women's health and to prioritize them for intervention studies aimed to maximize overall clinical benefit of HT and minimize their associated cardiovascular risk. Findings may also provide valuable insights into disease pathways and mechanisms, and identify novel targets for screening, prevention, and treatment of dyslipidemia and CVD in postmenopausal women.