Left ventricular hypertrophy (LVH) is a common phenotype, occurring in up to 60% of hypertensives that is associated with significant cardiovascular mortality. Ancillary to the Hypertension Genetic Epidemiology Network (HyperGEN) of the Family Blood Pressure Program (FBPP), we collected echocardiographic measures on 2,951 family members ascertained on hypertension, 652 randomly-selected subjects from the same source cohorts, and 247 family members ascertained for normotensive LVH. We identified several LVH linkage regions in affected hypertensive probands and siblings, fine mapped the regions, identified positional candidate genes, resequenced them to confirm haplotype tagging SNPs, and genotyped SNPs in unrelated LVH cases and controls. We found significant associations between LVH and all but one of the positional candidates (neuropeptide Y receptors 1, 2, and 5, carboxypeptidase E, interleukin-15, endothelin receptor A, peroxisome proliferator-activator receptor, retinoid receptor alpha, and secreted frizzled protein ? 2). For this renewal, we will further refine our linkage results by conducting linkage analyses that include the offspring of the hypertensive siblings who were recently genotyped by the Mammalian Genotyping Service (genotypes were released in October, 2005). Linkage analysis with these larger pedigrees will provide better power than was available to us previously. To further characterize linkage regions, we will use high-density (2 kb) SNP genotyping and conduct linkage disequilibrium mapping of these regions. For cost-efficiency, we will use the Affymetrix 500,000 SNP chip that provides genome-wide coverage, and use association methods in 500 unrelated cases-control pairs. We will replicate 5,000 SNPs in a second population from the FBPP (GENOA), and further characterize our 5 best regions. Finally, we will implement novel statistical methods for association studies. We hypothesize that we will identify genetic variants that play clinically significant roles in LVH, and that will suggest novel pathways for LVH preventive or therapeutic interventions. ? ? ? ?
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