The goal of this SCOR renewal is to build upon quantitative trait loci (QTLs) that they have identified to be in common in two human populations and in the rat to search for specific genes that importantly influence hypertension and related phenotypes. They propose four closely inter-related scientific projects (two human, one animal, and one theroretical) that bring together a team of geneticists, clinical investigators, physiologists, and biomathematicians. Building on the results of the QTL linkage analysis, Project 1 will study extended families from the largest """"""""closed population"""""""" in North America (Chicoutimi-Saguenay-Lac St. Jean, Canada). Regions of three selected QTLs found to be in linkage disequilibrium will be mapped with a family based association haplotype analysis using single nucleotide polymorphisms (SNPs) as genetic markers coupled with a transmission disequilibrium test (TDT). In Project 2, haplotype regions narrowed in the Canadian families within the area of likage disequilibrium will be utilized in a case-control study to identify genes in African Americans of Milwaukee using SNPs in positional candidate genes. Both clinical projects will build upon broad based phenotyping data to determine if distinct clusters of traits can be identified to stratify hypertensive subjects for further genetic analysis. Project 3 will build upon the extensive rat linkage analysis just completed and utilize chromosomal substitution (consomics/congenics) and expression profiling to examine the functional relevance of several specific QTLs and to identify differentially expressed genes of relevance within these regions. Project 4 focuses on the development of analytical tools to assess linkage and association data and to evaluate the functional significance of multiple haplotypes in genomic regions that influence blood pressure and associated traits. The proposed studies exploit novel Bioinformatic tools to more adequately characterize regions of homology between the rat and human genomes. The four Cores that will provide support for the SCOR include: Core B) Bioinformatics; Core C) Genomic; Core D) Biochemical Core.
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