GENETICS OF ESTROGEN AND CARDIOVASCULAR RESPONSES

该项目的目标是在Framingham心脏研究中调查雌激素受体和相关基因对动脉粥样硬化性心血管疾病(CVD)状态和结果的遗传贡献，以及对选择性雌激素反应调节剂(SERM)治疗心肌梗死(MI)后的反应。为了解决这些问题，我们将确定编码对雌激素反应起重要作用的蛋白质的基因变异，并测试这些变异与与心血管疾病、心肌梗死和缺血性心脏病恢复相关的特定临床参数之间的关系。首先，我们将对四个基因的遗传变异进行系统的筛选：雌激素受体α(ERα)、雌激素受体β(ERβ)、芳香酶(负责将睾酮局部转化为17-β雌二醇的酶)和SRC-1(典型的雌激素受体转录共激活因子)。我们将研究从随机选择的人群中抽取的1,000名男性和1,000名女性中，每个变量的频率与特定心血管功能参数的关系，弗雷明翰后代研究。这些研究将评估涉及DIN雌激素反应的关键基因的基因型与心血管功能之间的关系。此外，由于这一人群已经进行了纵向检查，心血管功能。此外，由于对这一人群进行了纵向检查，在同一个体绝经前和绝经后测量的心血管参数可以进行比较，这支持了对绝经后心血管参数变化与基因型之间关系的研究。对正常、非选定人群的研究将通过调查选择性雌激素受体调节剂(SERM)雷洛昔芬对治疗反应参数的遗传贡献来补充，该研究使用了本SCOR提案项目2中描述的150-200T-MI妇女的研究人群。在心肌梗死后人群中，我们还将评估一组基因中其他变异的作用，这些基因可能在决定心血管反应方面发挥重要作用。这组基因将包括血管扩张酶内皮型一氧化氮合酶(ENOS)和诱导型一氧化氮合酶(INOS)、血管收缩因子、内皮素-1、血管内皮生长因子(VEGF)、单核细胞趋化蛋白(MCP-1)、基质蛋白胶原和基质金属蛋白酶2(MMP2)、钙激活钾通道(BKCa)的基因。这些研究将为评估和理解基因对基于雌激素的心血管保护、病理和治疗反应的贡献提供一个框架。

The goal of this project is to investigate the genetic contribution of estrogen receptor and related genes to atherosclerotic cardiovascular disease (CVD) status and outcomes in the Framingham Heart Study, and to the response to post-myocardial infarction (MI) treatment with a selective estrogen response modulator (SERM). To address these questions, we will identify variations in genes that encode proteins that play a significant role in response to estrogen, and will test the relationship between these variants and specific clinical parameters relevant to CVD, MI and recovery from ischemic heart disease. Initially we will carry out a systematic screen for genetic variation in four genes: estrogen receptor alpha (ER alpha), estrogen receptor beta (ER beta), aromatase (the enzyme responsible for local conversion of testosterone to 17-beta estradiol), and SRC-1 (the prototypical estrogen receptor transcription co-activator). We will study the frequency of each variant in relation to specific parameters of cardiovascular function in 1,000 men and 1,000 women drawn from randomly selected population, the Framingham Offspring Study. These studies will permit an evaluation of the relationship between genotype for key genes involve din estrogen response and cardiovascular function. Furthermore, because this population has been examined longitudinally, cardiovascular function. Furthermore, because this population has been examined longitudinally, cardiovascular parameters measured on the same individual pre- and post- menopausally can be compared supporting the study of associations between genotype and post-menopausal changes in cardiovascular parameters. The study of a normal, unselected population will be complemented by investigation of the genetic contribution to parameters of response to treatment by a selective estrogen receptor modulator (SERM), raloxifene, using the study population of 150-200t-MI women from the clinical trial described in Project 2 of this SCOR proposal. In the post-MI population we will also evaluate the role of additional variants in a set of genes that are likely to play a significant role in determining cardiovascular response. This set of genes will include those for the vasodilator enzymes endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS), the vasoconstrictor, endothelin-1, the vascular endothelial growth factor (VEGF), monocyte chemotactic protein (MCP- 1), the matrix proteins collagen and matrix metalloproteinase 2 (MMP-2), the calcium-activated potassium channel, (BKCa). These studies will provide a framework for evaluating and understanding the genetic contribution to estrogen based cardiovascular protection, pathology and response to treatment.