The overall aim of this study is to identify genes influencing atherosclerosis as measured by coronary artery calcification (CAC), intimal medial thickness, and ankle brachial index, all quantitative measures of atherosclerotic burden, as well as endophenotypes for the atherosclerosis pathway in African-Americans. African-Americans are understudied, and yet have higher rates of many of the risk factors for atherosclerosis and CHD, lower quantitative CAC, but more hard CHD/CVD endpoints than Caucasians. We use the already collected, large (N=1,266), epidemiologically defined, longitudinal, broadly and deeply phenotyped (on all major atherosclerosis pathway domains) subjects from both the NHLBI Family Heart Study-SubClinical Atherosclerosis Network (FHS-SCAN) and the Johns Hopkins Family Heart Study. We will conduct a whole genome SNP scan, using the Illumina 650K Y-chip, which is specifically designed for subjects of African descent. We believe our family study allows optimization of several aspects of GW scan design in African- Americans. First, we will analyze the GW SNP data as an admixture map, which leverages information on individual and locus-specific ancestry, to enhance power to detect QTLs. Second, we will analyze the GW SNP data as an LD association scan, to more finely localize associated variants. Most importantly, family- based association analyses will allow us to strongly rule out false positives due to population stratification, a critical issue in African-American samples. Since the LD block structures for African-Americans are less well known than for other ethnic groups (they were not a primary target of the HapMap project), we will more finely genotype additional SNPs in hit regions, especially those in biologically plausible candidate genes, or in highly conserved regions, in order to better localize the signal. Further, we will combine the results from both the admixture map and the LD map analyses using a correlated meta-analysis technique. Our GW mapping approach has high power to detect any gene explaining at least 2-5% of a trait in the atherosclerosis pathway, through ht-SNPs that are at least within R2=0.80 of a functional variant. With the wealth of phenotypic characterization of FHS+JHFHS African-American subjects in pedigrees and the available linkage results, a genome-wide association scan would allow rapid and efficient discovery of genes related to the development of atherosclerosis in humans. Such findings would be of great significance: they could enhance our understanding of the metabolic and mechanistic processes that lead to atherosclerosis and coronary endpoints and, thereby, suggest possible points of intervention or therapy in the understudied, but high risk African- American population. ? ? ? ?
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