Genes of Oxidative Stress and Atherosclerotic Complications of Hypertension

描述（由申请人提供）：动脉粥样硬化是冠状动脉疾病（CAD）的主要原因，是美国男性和女性的最大单一杀手。氧化应激导致内皮功能障碍是高血压导致动脉粥样硬化过程的潜在因素。这个名为“氧化应激和高血压动脉粥样硬化并发症的基因”的项目提出了氧化应激途径基因变异在冠状动脉钙化（CAC）遗传结构中的作用，CAC是亚临床冠状动脉粥样硬化的一种衡量标准。本研究项目将使用基因网络方法来鉴定影响冠状动脉抵抗高血压损伤能力的基因。所有的DNA资源、CAD危险因素、体检数据和CAC措施已经从三个队列中提供给该项目。遗传多态性、协变量、高血压和亚临床冠状动脉粥样硬化之间的假设关系模型将使用CAC进行评估，CAC已经在来自罗切斯特，MN现场中心的动脉疾病遗传流行病学网络（GENOA）的个人或家族史的原发性高血压个体和来自冠状动脉钙化流行病学（ECAC）研究的个人或家族史的高血压个体中进行了测量。同样来自明尼苏达州罗切斯特。将在动脉粥样硬化多种族研究（MESA）的个体中寻求重复性发现的普遍性。我们将使用这种基于氧化应激基因网络的方法来超越单多态性效应，并研究单基因、基因间相互作用和基因与环境相互作用如何联合影响高血压患者或高血压风险增加的个体的CAC数量。

DESCRIPTION (provided by applicant): Atherosclerosis is the major cause of coronary artery disease (CAD), the single largest killer of American men and women. Oxidative stress leading to endothelial dysfunction is an underlying factor whereby hypertension contributes to the atherosclerotic process. This project entitled "Genes of Oxidative Stress and Atherosclerotic Complications of Hypertension" proposes to characterize the role of oxidative stress pathway gene variation in the genetic architecture of coronary artery calcification (CAC), a measure of subclinical coronary atherosclerosis. This research project will use a gene network approach to identify genes that influence the ability of the coronary artery to resist injury due to hypertension. All DNA resources, CAD risk factors, physical examination data and CAC measures are already available to this project from three cohorts. Models of the hypothesized relationships between genetic polymorphisms, covariates, hypertension and subclinical coronary atherosclerosis will be evaluated using CAC, already measured on individuals with a personal or family history of essential hypertension from the Genetic Epidemiology Network of Arteriopathy (GENOA), Rochester, MN fieldcenter and on individuals with a personal or family history of hypertension from the Epidemiology of Coronary Artery Calcification (ECAC) study, also from Rochester, MN. The generalizability of findings which replicate will be sought in the individuals of the Multi-Ethnic Study of Atherosclerosis (MESA). We will use this oxidative stress gene network-based approach to move beyond single polymorphism effects and investigate how single-genes, gene-by-gene interactions and gene-by-environment interactions combine to influence CAC quantity in individuals with hypertension or at increased risk of hypertension. PUBLIC HEALTH RELEVANCE Atherosclerosis is the major cause of coronary artery disease (CAD), the single largest killer of American men and women. Increasing our understanding of the role of genetic variation in sub-clinical coronary atherosclerosis in diverse populations can contribute to the earlier identification of individuals with increased susceptibility to clinical disease, the development of new, more efficacious treatments, and tailoring of treatments to those most likely to respond.