Arterial hypertension is a complex, multifactorial, polygenic and heterogenous disorder currently not characterized from a genetic viewpoint. The identification of the genes involved in this major health problem will certainly improve the detection, prevention, and treatment of the disease. The exploration of the genetic components of a complex disease like arterial hypertension is hampered by two major stumbling blocks: 1) the incomplete phenotying of patients and 2) the inadequacy of the sample size in view of the limited power of currently available genotyping techniques. The use of intermediate phenotypes is a strategy used to reduce the heterogeneity of a complex disease and facilitate the identification of putative genes. A fairly large number of hypertensive patients, especially African Americans, display an amplified hypertensive response in a salt-rich environment. We hypothesize that this intermediate phenotype of salt-sensitivity is an inherited trait which is instrumental in the development of hypertension and is a risk factor for increased morbidity and mortality, as suggested by studies conducted in African American and Japanese populations. The factors underlying this exaggerated blood pressure response to salt are poorly defined. We propose in the present application to identify the anthropometric, humoral, hormonal, hemodynamic and renal phenotypic markers of salt sensitivity and pave the way to future and powerful genotyping by conducting the following lines of research: 1. To perform, on an ambulatory basis, a comprehensive but practical phenotyping of 500 hypertensive patients from the Cleveland metropolitan area. 2. To identify the phenotypic markers aggregating with salt sensitivity. 3. To isolate and store DNA and lymphocyte samples from these subjects and their parents. These samples will be used by the genotyping center at CWRU for future genome scan, when more powerful techniques like single nucleotide polymorphisms (SNPs) and digital genetic analysis become available. This project intends to answer the following questions: 1. Can we identify a set of robust phenotypic criteria defining salt-sensitivity using an outpatient protocol? 2. What are the genes underlying salt sensitivity and the risk of developing arterial hypertension? The identification of the phenotypic and genetic determinants of salt sensitivity may lead to: 1. The early detection of subjects at risk. 2. The implementation of new preventive interventions in hypertensive patients and their relatives. 3. The selection of the most appropriate treatment based on pharmacogenetic parameters. """"""""
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