In this proposal, we will employ several synergistic strategies to identify novel genetic determinants of hypertension. Our primary strategy will be to use genomic markers (both anonymous markers and candidate genes) spanning the human genome at an average density of 10 cM to examine 250 white sibships in Tecumseh, MI for genetic linkage with blood pressure and the intermediate phenotypic features of elevated erythrocyte lithium- sodium countertransport, the hyperkinetic hyperadrenergic state, decreased proximal tubular lithium clearance (a measure of proximal tubular sodium handling), and elements of the renin-angiotensin system (plasma renin and angiotensin-converting enzyme activity and serum angiotensinogen concentration). Positive findings will be confirmed by further testing for linkage in a population of 250 African-American sibships in Maywood, IL. In addition, we will seek to develop new candidate genes for hypertension by identifying genes linked to the hypertensive phenotype in segregating rat populations derived from inbred normotensive and hypertensive strains; homologues of genes identified in rats will be searched for in humans. Having developed and refined important candidates in our sibships and rat models, we will test associations in several extant black populations in Jamaica and Nigeria as well as in subjects in Tecumseh and Maywood selected from the extremes of the populational blood pressure distribution. To carry out these investigations, we have brought together well- characterized population resources suitable for the identification of probands and families affected by hypertension (Tecumseh, MI and Maywood, IL), two experienced teams of epidemiological investigators at the University of Michigan and Loyola University of Chicago, state-of-the-art genotyping facilities run by experienced investigators at Case Western Reserve University, a superb team of statistical geneticists, an animal resource with a proven record of productivity in identifying genetic loci regulating blood pressure in hypertensive rats, and several relevant population resources suitable for case-control studies (Nigeria, Jamaica). We are confident that these resources will permit us to accomplish our primary aim of identifying genetic determinants of hypertension.
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