The overall goal of this proposal is to identity genetic determinants of hypertension by testing the primary underlying hypothesis that high blood pressure (BP) in Mexican-Americans (MA) is linked genetically and/or physiologically to insulin resistance (IR). We propose to test this hypothesis by linkage analysis of a soon to be completed systematic genome-wide scan, followed by fine mapping, testing positional candidate genes and performing linkage disequilibrium studies in chromosomal regions demonstrating linkage. We have previously performed extensive phenotyping of family members ascertained via MA subjects with documented hypertension. This phenotyping, conducted in a 4-day GCRC protocol, included an assessment of BP, IR (by glucose clamp), and its related metabolic traits, and carotid intimal-medial wall thickness, all of which were highly heritable. 930 individuals in 160 nuclear families, resulting in 800 sibpairs, have been phenotyped and immortalized cell lines established. Our initial linkage analysis of the genome scan data on the first 390 individuals has identified several promising areas for linkage of BP and IR on chromosomes 1, 2, 7, and 17. In the first Aim, we propose to confirm chromosomal regions which contribute to the regulation of BP and related intermediate phenotypes of IR by linkage analysis of the soon to be completed systematic genome scan in the previously phenotyped families.
The second Aim will be to fine map the chromosomal regions with the best support for linkage based on multiple criteria: the strength of the linkage evidence, the coincident mapping of different intermediate phenotypes/quantitative traits, and comparison to findings in the literature. After prioritizing the loci, the third Aim will test positional candidate genes (in BP physiology, cardiovascular complications, insulin action, and glucose and lipid metabolism) in these chromosomal regions by family based association methods, i.e. quantitative transmission disequilibrium testing. For important linkage areas without obvious candidate genes, the fourth Aim will use dense polymorphic markers in linkage disequilibrium analysis. Due to its ethnic history, the MA population is particularly well suited to this approach. In the fifth Aim, as specific loci and/or genes are identified, we will test for interaction effects on the quantitative traits of interest. Identification of such interactions will aid in the elucidation of physiologic pathways leading to disease. Our long term goal is to understand the manner by which these genetic variations affect BP physiology and pathophysiology, leading eventually to new therapies, disease management, and preventive interventions.
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