from application) This application is a response to an RFA on longitudinal genetic epidemiologic studies on aging. The goal of this application is to provide the foundation to identify specific gene mutations involved in changes with aging of cardiovascular phenotypes and how these gene mutations interact with the environment to determine the rate of aging and absence or presence of disease. The study population consists of 98 large, multigenerational Utah pedigrees of 2500 individuals. These individuals already have been examined up to three times over 10 years (starting in 1980) with a wide variety of phenotypes measured, including environmental risk factors for cardiovascular disease. There were four themes in the biochemical variables collected: The renin-angiotensin-aldosterone system, the kallikrein-prostaglandin system, the cellular ion transport systems, and the multiple metabolic syndrome including abnormal lipids, insulin and obesity. Additional collected variables associated with aging include blood pressure, heart rates, body temperature, albumin, bilirubin, uric acid, glucose. C-reactive protein and apoA-IV will be measured. Other strengths are 400 anonymous genetic markers being genotyped at the Mammalian Genotyping Service on almost 2000 of these persons. The combination of a large array of phenotypes and genotypes in large pedigrees from a low-risk Utah population provides a unique setting to study the genetic epidemiology-of aging. The goals of this pilot study are to analyze the newly obtained genetic marker data to identify chromosomal regions linked to each of the measured phenotypes and 10-year longitudinal changes in phenotypes. Environmental factors related to the phenotypes will be analyzed and those that are significant will be tested for interactions with these genetic regions within segregation/linkage models. Candidate genes will be prioritized from these regions. In addition, we will collect 20-year follow-up medical history data on each subject to obtain the number of death and incident cardiovascular events (CHD, stroke, diabetes, hypertension). These data will be used for survival analyses. We will assess the feasibility of performing a 25-year follow-up fourth exam during a full-scale study, in which all measured phenotypes at the first and second visits will be remeasured. Twenty-five year changes in these variables will provide an extremely powerful setting to identify specific genes related to aging changes in cardiovascular risk factors.
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