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.