GENETICS OF ESTROGEN AND CARDIOVASCULAR RESPONSES

雌激素和心血管反应的遗传学

• 批准号: 6570514
• 负责人: David Housman
• 金额: $ 31.63万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6570514
• 关键词: aromatase; atherosclerosis; cardiovascular function; collagenase; endothelin; estrogen receptors; estrogens; family genetics; gene expression; gene frequency; genotype; hormone regulation /control mechanism; human data; longitudinal human study; metalloendopeptidases; monocyte chemoattractant protein 1; myocardial ischemia /hypoxia; nitric oxide synthase; polymerase chain reaction; population genetics; postmenopause; potassium channel; single strand conformation polymorphism; vascular endothelial growth factors; vasoconstrictors

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.

该项目的目的是研究雌激素受体和相关基因对弗雷明汉心脏研究中的动脉粥样硬化心血管疾病（CVD）状态和结果的遗传贡献，以及对腰椎后梗死（MI）治疗的反应，通过选择性雌激素反应调节剂（SERM）。为了解决这些问题，我们将确定编码蛋白质在雌激素中起重要作用的蛋白质的变化，并将测试这些变体与与CVD，MI和缺血性心脏病相关的特定临床参数之间的关系。最初，我们将进行四个基因遗传变异的系统筛选：雌激素受体α（ERα），雌激素受体β（ERβ），芳香族酶（负责将睾丸激素转化为睾丸激素到17-Beta雌二醇）和SRC-1（原始雌激素受体受体转录Co-Accrcription）。我们将研究每种变体的频率与1,000名男性和1,000名从随机选择人群中的女性（Framingham后代研究）中的特定参数相关的频率。这些研究将允许评估关键基因基因型之间的关系，涉及DIN雌激素反应和心血管功能。此外，由于该人群已纵向检查心血管功能。此外，由于已经纵向研究了该人群，因此可以比较在同一个体前后测量的心血管参数，以支持基因型与心血管参数的绝经后变化之间关联的研究。使用选择性雌激素受体调节剂（SERM）（raloxifene）对遗传贡献的遗传贡献的研究将得到对正常，未选择的人群的研究，使用了该SCOR建议项目2中的临床试验中描述的150-200T-MI女性的研究人群。在MI后人群中，我们还将评估一组可能在确定心血管反应中起重要作用的基因中其他变体的作用。 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），钙活化的钾通道（BKCA）。这些研究将提供一个框架，以评估和了解对基于雌激素的心血管保护，病理和对治疗的反应的遗传贡献。