The long-term goal of the Strong Heart Family Study is to detect and map polymorphic genes that influence variation in risk factors for cardiovascular disease and other related disorders that are major health problems in American Indians. Of immediate interest are risk factors and precursors such as plasma concentrations of lipoproteins, apolipoproteins, insulin, glucose, urine albumin excretion, measures of obesity, measures associated with hemostasis, and measures of cardiac and arterial structure and function. In the pilot study during the current grant period, we have collaborated with the other Strong Heart Study (SHS) investigators in successfully recruiting and examining more than 300 members of extended families in each of the three centers (in Arizona, Oklahoma, and the Dakotas). We have shown that many of the CVD-related phenotypes are heritable, and we are generating a 10 centimorgan map that we are using in preliminary linkage analysis to localize CVD risk factor genes. We are encouraged by the success of the pilot study. To provide adequate power to detect and map CVD risk factor genes in each center and to localize genes that are important across tribal groups, we propose to recruit 900 additional members of approximately 30 extended families in each center, ascertained through SHS participants. We will estimate heritabilities, effects of covariates, household and center effects, and genetic and environmental correlations for a large set of CVD risk factor phenotypes. We will generate a 10 centimorgan map that includes genotyping of 386 short tandem repeats (STRs) in each of the 2700 individuals, and screen the phenotypes for linkage using a variance component approach. We will do finer scale mapping with additional STRs to more precisely localize quantitative trait loci (QTLs) within targeted chromosomal regions, and use SNPs in positional candidate genes for linkage/association analysis to identify genes that are responsible for linkages detected by the initial genome scan. The Southwest Foundation investigators will continue to direct the design of the Family Study, will identify families to recruit, will serve as a resource for questions concerning recording of family data, directions in which to expand families, etc., and will be responsible for genotyping and statistical genetic analysis. This study will form the basis for future studies aimed at identifying and characterizing the genes that influence CVD risk factors in American Indians.
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