This application aims to identify gene variants in chromosome 17 associated with blood pressure variation and susceptibility to hypertension, by following-up persuasive linkage findings of blood pressure in American Indian participants of the Strong Heart Family Study (SHFS). Prior genome-wide linkage analysis of 1894 SHFS participants detected evidence of a quantitative trait loci (QTL) influencing systolic blood pressure on chromosome 17q25.3. This region has been also identified in the Family Blood Pressure Program (FBPP) Hypertension Genetic Epidemiology Network (HyperGEN) and FBPP Genetics Epidemiology Network of Atherosclerosis (GENOA) participants for blood pressure-related traits and, therefore, may harbor genes with broad significance for blood pressure regulation. We propose to extend this work by comprehensively evaluating genetic variation in this chromosome 17q region in the large and informative cohort of the SHFS using state-of-the-art molecular and statistical genetic analyses. We will test the hypothesis that the chromosome 17 QTL contains one or more polymorphic variants that account for the linkage signal by performing comprehensive linkage disequilibrium mapping of the region in the SHFS samples. For genes with preliminary evidence of association, we will select the most promising candidate genes for resequencing and single nucleotide polymorphism (SNP) discovery. We will use the measured genotype approach and family based association to test for association of identified SNPs and/or haplotypes with our linked traits, while accounting for linkage. We plan to replicate our findings in the FBPP HyperGEN (N=3,855) and GENOA (N=5,174) samples of European American, African American and Hispanic American subjects. The prior findings of linkage of blood pressure traits to 17q in the FBPP population samples to be used for replication are exciting and may allow us to successfully identify gene variants influencing blood pressure and hypertension susceptibility. Identification of the risk alleles underlying this linkage peak may suggest novel mechanisms underlying blood pressure regulation and the development of hypertension.
Given the extensive morbidity associated with hypertension in the US and around the world, understanding its genetic basis is a critical step toward disease mitigation and treatment. The importance of studying hypertension in an American Indian population is highlighted by this population's elevated risk of cardiovascular disease, in addition to the gap in the literature for this relatively understudied group. The proposed study may expand our understanding of the impact of the genes on the natural history of hypertension and mechanisms of blood pressure control.
