The goal of this SCOR is to identify genetic loci and specific genes whose expression results in hypertension and in important phenotypic changes associated with hypertension. We have proposed 4 closely inter- related scientific projects, two human, one animal, and one theoretical development of mathematical tools for analysis, which brings together a team of uniquely qualified geneticists, clinical investigators, physiologists, and biomathematicians. Project 1 will conduct a linkage analysis, using a total genomic search strategy, in 400 African American sib pairs from Milwaukee/Chicago in which each sibling has hypertension and hypercholesterolemia. Hypertension associated phenotypes (renal function, renal and peripheral vascular sensitivity, stress responses) will be studied in 200 of these sib pairs. An unrelated African American control group will be used in association studies to determine which loci and risk factors contribute most to hypertension in this population. Project 2 will conduct a genome wide search of 200 similarly affected sib pairs obtained from a unique population of genetic isolates residing in the Chicoutimi Provence in Canada. The general linkage analysis will be refined by determining mutations that exist in linkage disequilibrium. Project 3 will conduct a genome wide search of an F2 population of inbred rats (Dahl S/jr x Brown Norway) to define hypertension susceptibility loci and loci influencing renal and vascular function. Additionally, congenic rat strains will be constructed that differ only in the region of individual loci that are linked to hypertension in order to study the physiological mechanisms by which the expression of this locus influences blood pressure. Homologous genetic loci which are found to influence blood pressure and/or important hypertension associated phenotypes in the F2 rat cross will be used as candidate genes in the human populations. Project 4 will design and apply analytic tools to be used in the gene mapping of studies of Projects 1-3 and develop novel extensions of traditional gene mapping methods for complex traits, accounting for heterogeneity and effects of concomitant variables such as age, sex, and shared environment. Novel techniques to analyze the dynamic nature of blood pressure will be undertaken in order to detect additional hypertension associated phenotypes. The four Cores which will provide support for the entire SCOR include: A) Administrative Core (Milwaukee); B) Informatics and Computational Resources (Milwaukee); C) Genotyping Core (Boston); D) Biochemical Core (Milwaukee)
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