MOLECULAR GENETICS OF ATHEROSCLEROSIS

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The overall goal of Project 2 is to perform a genome-wide search to identify and localize genes that affect quantitative measures of atherosclerosis, NIDDM, and obesity in Mexican American families. The particular focus of Project 2 is on localization of major genes that have been detected in the current grant period, major genes that account for 30% or more of the variance in many of these quantitative measures. In Project 2, each of 1,400 family members will be typed for 391 multiplexed short tandem repeat (STR) polymorphisms spaced at approximately 10 cM intervals. An initial statistical screen will be performed using a sibship-based variance component method to identify possible linkage with quantitative phenotypes. When preliminary evidence for linkage is detected (p less than 0.05), Project 1 (atherosclerosis traits) and Project 3 (NIDDM and obesity traits) will perform more extensive linkage analyses. When suggestive evidence for linkage is obtained (lod greater than 1.9), Project 2 will type additional closely spaced markers in the chromosomal region, for subsequent multipoint linkage and gametic disequilibrium analyses to more precisely localize genes affecting quantitative risk factors. The human gene map will be consulted to determine whether candidate genes are located in that chromosomal region, and such genes will be subjected to molecular analyses to determine structural and functional differences that underlie allelic effects.