Determinants of arterial function in hypertension

描述（由申请人提供）：动脉疾病（动脉硬化）在高血压的存在下加速，高血压是影响美国6500多万人的主要心血管风险因素，每年导致约1100亿美元的医疗保健费用。尽管在动脉疾病的治疗方面取得了显著进展，但由于高血压引起的靶器官损伤和心血管事件继续造成重大的卫生保健负担。靶器官损伤和动脉事件（如心肌梗死和中风）通常在没有警告的情况下发生，但在动脉异常之前发生 动脉硬化和内皮功能障碍 可以非侵入性地评估。在本申请中，我们提出鉴定与动脉硬度（主动脉脉搏波速度和主动脉增强指数）和内皮功能（肱动脉血流介导的扩张和反应性充血）的测量中的个体间变化相关的蛋白质组学和基因组标记物。拟议研究的参与者将包括属于动脉病遗传流行病学网络（GENOA）研究的高血压同胞的特征明确的非裔美国人（n = 1000）和非西班牙裔白色（n = 1000）受试者，该研究是一项多中心研究，旨在确定影响高血压水平和靶器官损伤的基因。本提案可利用的是GENOA研究的临床研究基础设施和以下广泛收集的蛋白质组学和基因组标记物：a）血管疾病病因学途径中的50种蛋白质组学标记物，包括炎症、凝血、氧化应激、脂蛋白代谢和血压调节; B）387个跨越基因组的微卫星标记，和c）在血管疾病的病因学途径中的150个候选基因中的1500个双等位基因多态性。将实现以下具体目标：目标1。确定血管疾病病因学途径中的50种循环蛋白质组标记物是否与动脉功能非侵入性测量中的个体间差异相关。目标二。使用连锁分析确定跨越基因组的387个微卫星标记中的任何一个是否与影响动脉功能测量中个体间差异的基因组区域相关联。目标3：确定血管疾病病因学途径中150个候选基因的1500个双等位基因多态性是否影响动脉功能非侵入性测量的个体间差异。公共卫生相关性。动脉疾病是美国死亡率和发病率的主要原因。我们研究的目的是鉴定影响动脉功能的新蛋白质和基因。这项工作将有助于确定那些有患动脉疾病风险的人，并促进新疗法的开发。

DESCRIPTION (provided by applicant): Arterial disease (arteriosclerosis) is accelerated in the presence of hypertension, a major cardiovascular risk factor that affects more than 65 million people in the USA, resulting in health care costs of ~$110 billion annually. Despite significant advances in the treatment of arterial disease, target organ damage and cardiovascular events due to hypertension continue to impose a major health care burden. Both target organ damage and arterial events such as myocardial infarction and stroke, often develop without warning but are preceded by arterial abnormalities arterial stiffness and endothelial dysfunction that can be assessed non- invasively. In this application, we propose to identify proteomic and genomic markers that are associated with inter- individual variation in measures of arterial stiffness (aortic pulse wave velocity and aortic augmentation index) and endothelial function (brachial artery flow-mediated dilatation and reactive hyperemia). Participants in the proposed study will include well-characterized African American (n = 1000) and non-Hispanic white (n = 1000) subjects belonging to hypertensive sibships of the Genetic Epidemiology Network of Arteriopathy (GENOA) study, a multi-center effort to identify genes influencing blood pressure levels and target organ damage in hypertension. Available to the present proposal is the clinical research infrastructure of the GENOA Study and the following extensive collection of proteomic and genomic markers: a) 50 proteomic markers in etiologic pathways of vascular disease including inflammation, coagulation, oxidative stress, lipoprotein metabolism, and blood pressure regulation; b) 387 microsatellite markers spanning the genome, and c) 1500 diallelic polymorphisms in 150 candidate genes in the etiologic pathways of vascular disease. The following specific aims will be accomplished: Aim 1. Determine whether 50 circulating proteomic markers in etiologic pathways of vascular disease are related to inter-individual variation in non-invasive measures of arterial function. Aim 2. Identify, using linkage analyses, whether any of the 387 microsatellite markers spanning the genome are linked to genomic regions that influence inter-individual variation in measures of arterial function. Aim 3. Determine whether 1500 diallelic polymoprphisms in 150 candidate genes in etiologic pathways of vascular disease influence inter-individual variation in non-invasive measures of arterial function. PUBLIC HEALTH RELEVANCE. Arterial diseases are the leading cause of mortality and morbidity in the US. The aim of our investigation is to identify novel proteins and genes that influence arterial function. Such work will help in identifying those at risk of developing arterial disease and facilitate development of new therapies.