DESCRIPTION (provided by applicant): Coronary artery disease (CAD) is the number one cause of death and mortality world-wide. High levels of serum triglycerides (TGs) and low levels of serum high-density lipoprotein cholesterol (HDL-C) are major risk factors for CAD. Previous epidemiological studies have shown that these two lipid disturbances are the two most common dyslipidemias in Mexicans. However, the genetic factors underlying high serum TGs and low HDL-C are underinvestigated and poorly identified in Mexicans. As the Mexican-American and the genetically related Latin-American populations represent the fastest growing minority in the United States, elucidation of the unknown genetic factors influencing the increased susceptibility of Mexicans to these common dyslipidemias is of great relevance to these U.S. minorities and the American healthcare system. Genome-wide association studies (GWAS) of complex cardiovascular traits are becoming the method of choice to identify novel risk variants. However, the Mexican population has thus far not been represented among these GWAS. Furthermore, no information about genome-wide linkage disequilibrium (LD) structure is available in Mexicans, as the publicly available HapMap data cannot be directly applied for the admixed Mexican population descended from a recent mix of Amerindian and European ancestry with a small proportion of African ancestry. The major goal of this application is to identify the DNA sequence variants that form the high genetic predisposition of Mexicans to elevated serum TG levels and related atherogenic metabolic traits such as low HDL-C using 4400 Mexican hypertriglyceridemic cases and controls, collected at the INCMNSZ, and a large Mexican population-based national survey with 41,207 subjects, collected in 2000 as the National Survey sample by the Institute for Public Health of Mexico. We propose to perform a GWAS in Mexican high TG cases and controls in two stages (Specific Aim 1). Gene expression data from fat biopsies from 50 Mexican subjects with hypertriglyceridemia and 50 with normolipidemia will be utilized as an additional filter to select DNA variants for stage 2 of the GWAS. In Specific Aim 2, we propose to investigate the variants identified as significant in the GWAS for risk, gene-gene and gene-environment interactions at the population level in 41,207 Mexicans. While Specific Aims 1-2 are targeted to identify common DNA variants, in Specific Aim 3 we propose to identify all existing rare variants by extensive resequencing of the genes implicated for high TGs in Mexicans. Accomplishing these Specific Aims should help us identify the susceptibility variants predisposing the Mexicans for high TGs.

Narrative The Mexican population has a high predisposition to elevated serum triglycerides. However, the genetic factors underlying this increased susceptibility are underinvestigated and poorly identified. The major goal of this proposal is to perform a genome-wide association study in Mexicans to identify DNA sequence variants for high serum triglycerides and to determine the population risks related to the identified variants in a large Mexican population-based national survey.