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: The primary objective of this study is to test the hypothesis that the PC-1 gene is involved in the insulin resistance, and therefore contributes to the development of type 2 diabetes mellitus (T2DM) in Mexican Americans. If an association is observed between polymorphisms within, or near, the PC-1 gene and insulin resistance, and nearby genes can be excluded, further functional studies will be pursued. These include examination of PC-1 mRNA stability and expression levels, and direct measurement of insulin receptor tyrosine phosphorylation levels in CHO/IR cells co-expressing the insulin receptor and PC-1 variants. RESEARCH PLAN AND METHODS: State-of-the-art methods will be used to quantitate insulin receptor tyrosine phosphorylation, thereby defining the insulin resistance phenotype at the molecular level. Single nucleotide polymorphisms (SNPs) will be identified by direct DNA sequencing of the PC-1 gene in individuals with normal (N=10) and impaired (N=10) skeletal muscle insulin receptor phosphorylation. High-throughput assays will be designed to screen SNPs with allele frequencies 10%. Selected SNPs will be screened within a larger population sample of Mexican Americans (N=1137) derived from the SAFADS and GENNID studies. SNP genotypes will be statistically analyzed for association with insulin receptor tyrosine phosphorylation, insulin resistance, and other T2DM phenotypes. Linkage data will be utilized in cutting-edge combined linkage/linkage disequilibrium analyses with these SNPs to detect functional variants, which may underlie the observed linkage peak. CLINICAL
Mexican Americans represent approximately 52% of the San Antonio population. This population has an extremely high prevalence of T2DM, and an improved understanding of the underlying genetic mechanisms of T2DM, therefore, well serves the needs of this population. In this ethnic group insulin resistance is severe and is well established before the onset of overt diabetes. Functional studies have established that mutations within the PC-1 gene lead to impaired insulin signaling. These studies provide convincing evidence of a direct mechanism for PC-1 involvement in insulin resistance. The gene is located within a chromosomal region that has been genetically linked to insulin resistance in Mexican Americans in the San Antonio Family Diabetes Study (SAFADS). The linked region, on the long arm of chromosome 6, produced a logarithm of the odds (LOD) score of 5.8 for linkage with a bivariate insulin resistance/obesity phenotype (leptin + HOMA IR). This is one of the strongest genetic signals ever recorded for a common multifactorial disease. Within this highly significant region, PC-1 is the strongest positional candidate gene and highly likely to be an important susceptibility gene for insulin resistance/T2DM in this at-risk population.
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