Hypertension is a complex disorder whose expression is determined by numerous genetic as well as environmental factors. The problem of identifying the genes involved is complex. Studies of hypertension in human subjects are complicated by non-Mendelian inheritance, genetic heterogeneity, a late age of onset, incomplete penetrance, and environmental influences. However, recent advances, including the increased ability to delineate the disordered physiology related to hypertension, the discovery of highly polymorphic molecular genetic markers, the development of new strategies for analysis of complex genetic disorders, the development of the relevant statistical programs, and the ready availability of much faster computers, have put the identification of genes making even relatively modest contributions to the disease within reach. The goal of Project 2 is to identify specific genes and regions within the human genome contributing to blood pressure regulation and intermediate hypertension phenotypes, with particular emphasis on insulin resistance and salt sensitivity. We will search for genetic loci by systematically mapping the entire human genome using highly polymorphic molecular markers in approximately 200 extensively phenotyped Mexican American families with over 600 sibpairs. These families will be ascertained via a proband with hypertension. A systematic mapping approach is particularly appropriate since there are so many potential candidate genes for blood pressure regulation. Although an alternative approach would be to first study all of these candidate genes, the methodology necessary for directly studying candidate genes (ie RFLP analysis, frequently requiring Southern blotting) is costly and inefficient. We therefore propose to begin with a systematic mapping approach, followed by targeted study of only those candidate genes that map within regions of interest identified by the systematic mapping. Once candidate gene regions are identified by systematic mapping, more detailed linkage analyses of specific candidate genes within these regions, as well as fine mapping of regions without known candidate genes, will be undertaken.
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