TRANSLATIONAL GENOMICS RESEARCH INSTITITUE, THE

Coronary heart disease, arising mainly from dysregulated lipid metabolism, is the leading cause of death among individuals with type 2 diabetes mellitus. Although lipid levels are strongly dependent upon genetic factors, and numerous genetic variants underlying monogenic lipid disorders have been identified, genetic determinants of lipid levels in both the general population and in individuals with type 2 diabetes remain unknown. In families ascertained for type 2 diabetes who participated in the American Diabetes Association- sponsored Genetics of Non-Insulin Dependent Diabetes (GENNID) study, we have found evidence of linkage for triglyceride-to-HDL ratio on chromosome 3p12.1-q13.31 (LOD=3.36) in Caucasians and 11p15.4-p11.3 (LOD=2.45) in Hispanics. Evidence for linkage was also found on 19p13.2-q 13.42 for total cholesterol (LOD=2.26) in African Americans. Each of these regions has been implicated in the control of lipid levels in at least three independent populations. We hypothesize that 3p12.1-q13.31, 11p15.4-p11.3, and 19p13.2- q 13.42 harbor genes which modulate lipid traits in individuals with type 2 diabetes. We propose to address this hypothesis by first refining the regions of linkage on chromosomes 3, 11, and 19, which will narrow the linkage interval and increase information content, followed by a targeted characterization of genes located within each region to identify variants that underlie lipid traits. The genetic variants identified will be tested for association with plasma lipid concentrations in Caucasian, Hispanic, and African American families from the linkage study and variant effects on linkage will be assessed. To identify potential lipid-related variants that might be missed in a targeted gene approach in the region of strongest linkage, a gene-based linkage disequilibrium map of the chromosome 3 linked intervals will be established. Relevance of research to public health: Lipid levels are under the control of genetic factors. The goal of this proposal is to advance our understanding of lipid abnormalities associated with type 2 diabetes mellitus through identification of lipid-related loci which have been linked to specific chromosomal regions. Identification of genes that regulate lipid levels will enhance our understanding of the inheritance of lipid- related traits, provide markers to target individuals at greatest risk for developing heart disease, and potentially lead to improved treatment strategies for dyslipidemia.

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