GENETIC MAPPING OF ATHEROSCLEROSIS PHENOTYPES

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The objective of Project 1 is to map genes that influence quantitative phenotypes related to the development of atherosclerosis in Mexican American families in the San Antonio Family Heart Study. A genomic search, utilizing a 10 centimorgan map of 391 short tandem repeat markers distributed throughout the genome, will be conducted to determine the chromosomal locations of six major genes detected during the current grant period (gene influencing HDL-C,LDL-C, apoAI, apoB, SHBG, and DHEAS). For lipoprotein phenotypes for which no major genes have yet been detected, evidence for major gene effects will be sought. The genomic search will focus on chromosomal regions that show preliminary evidence for linkage in sibship based variance component screening tests in Project 2. If warranted, the analyses will be expand to include additional DNA markers in these regions. Genetic effects on carotid and fibrinolysis phenotypes will be quantified using data from a recall of 750 family members. Full pedigree variance component analysis as well as penetrance-based methods will be used in a genomic search to determine the chromosomal locations of genes that influence these phenotypes. For DNA markers that give suggestive evidence of linkage, analyses will be expanded to include additional markers in these regions, utilizing multipoint methods. To improve genetic models, strengthen evidence for linkage, and reduce the number of false positives, gxE interactions and pleiotropic and epistatic effects of major genes will be quantified. Oligogenic analysis will strengthen linkage signals and further reduce false positives, and disequilibrium analysis will improve localization of genes influencing quantitative CVD risk factors. Genes localized in Project 1 will guide the selection of candidate genes for molecular studies in Project 2. These analyses will set the stage for future efforts to identify the major genes and understand their functions.