GENETICS OF ESTROGEN AND CARDIOVASCULAR RESPONSES

本项目的目的是研究雌激素受体和相关基因对Fracheart研究中动脉粥样硬化性心血管疾病（CVD）状态和结局的遗传贡献，以及对心肌梗死后（MI）选择性雌激素反应调节剂（SERM）治疗的反应。为了解决这些问题，我们将确定编码蛋白质的基因的变异，这些蛋白质在对雌激素的反应中起着重要作用，并将测试这些变异与CVD，MI和缺血性心脏病恢复相关的特定临床参数之间的关系。最初，我们将对四个基因的遗传变异进行系统性筛查：雌激素受体α（ER α），雌激素受体β（ER β），芳香酶（负责将睾酮局部转化为17-β雌二醇的酶）和SRC-1（原型雌激素受体转录共激活因子）。我们将在随机选择的1,000名男性和1,000名女性中研究每种变异的频率与心血管功能的特定参数之间的关系，这是一项Fragrance Offspring研究。这些研究将有助于评价参与雌激素反应和心血管功能的关键基因的基因型之间的关系。此外，由于该人群已被纵向检查，心血管功能。此外，由于对该人群进行了纵向检查，因此可以比较绝经前和绝经后对同一个体测量的心血管参数，支持研究基因型与心血管参数绝经后变化之间的相关性。将通过研究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，对正常、高血压人群的研究进行补充，使用来自本SCOR提案项目2中描述的临床试验的150- 200 t-MI女性研究人群。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舒张酶内皮一氧化氮合酶（eNOS）和诱导型NOS（iNOS）、血管收缩剂内皮素-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（MMP-2）、钙激活钾通道（BKCa）的基因。这些研究将为评估和理解雌激素对心血管保护、病理学和治疗反应的遗传贡献提供一个框架。

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.