This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: This Program Project supports the San Antonio Heart Study, a comprehensive genetic epidemiological study of atherosclerosis and its correlates in Mexican Americans. The long-term goal is to detect, map, characterize, and identify new polymorphic genes that influence variation in susceptibility to cardiovascular disease. RESEARCH PLAN AND METHODS: More than 1400 members of 41 extended Mexican American families were recruited without regard to disease status and examined during the first grant period (SAFHS1), and 850 members of the larger families were recalled during the current grant period (SAFHS2). Genotyping of all family members for 414 markers in a 10 centimorgan map will be complete by the end of the current grant period. Using data from nearly 500 members of 10 of the largest families (Pedigree Set A), we have detected and mapped quantitative trait loci (QTLs) influencing leptin, fat mass, BMI, pro-ACTH, insulin, 2 hour glucose, LDL3-C, HDL-C, HDL2a unesterified cholesterol, several measures of median HDL particle size, P-selectin, and VCAM-1. For regions with the strongest evidence for linkage, additional, more closely spaced markers are being typed for use in finer scale mapping strategies. CLINICAL
With the completion of the genome scan for the remaining family members, we are poised to take advantage of the valuable resource created during the past 10 years. In the proposed grant period (SAFHS3), we will seek to map and characterize QTLs for existing phenotypes for which strong signals were not detected in the smaller data set, as well as new phenotypes assessed during the recall. We will pursue our most promising leads, refining linkage signals, characterizing interactions and pleiotropic effects of these genes, and identifying them. We will also target novel phenotypes of the adipo-insular axis and phenotypes related to inflammation and oxidative stress. These new phenotypes, as well as glucose, insulin, total and HDL cholesterol, lipoprotein size phenotypes, and leptin, will be assessed in a recall of 859 family members. Taking advantage of our 5- and 10-year longitudinal data, we will seek genes that influence age-related changes in CVD risk factors.
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