We have carried out a detailed genetic evaluation of the 20q12-q13.1 diabetes susceptibility region of chromosome 20. Results of this study are: 1. evidence for association of one gene, PTPN1, with type 2 diabetes susceptibility and metabolic measures of insulin resistance, and 2. evidence for association with type 2 diabetes of at least 2 other genomic segments in this region. In this renewal application we propose to determine the molecular genetic basis for PTPN1 gene association with T2DM through comprehensive DMA sequencing of the 100 kb PTPN1 haplotype block associated with type 2 diabetes and insulin resistance. This data will supplement SNP data available in existing databases. The resulting comprehensive database of genetic variation in this region, i.e. an """"""""ultra high density"""""""" SNP map, will be the basis for identifying new PTPN1 haplotypes and will determine whether association to diabetes phenotypes is due to a single SNP, a small number of SNPs, or an extended haplotype encompassing most or the entire haplotype block. Expanded genetic analyses in multiple additional populations will establish the extent to which PTPN1 contributes to diabetes phenotypes in the general population and explore the effect of phenotypic traits (e.g. BMI) on the genetic association. In addition, several other 20q12-13 regions with evidence of association to T2DM will be subjected to detailed molecular genetic analysis to determine if they are true T2DM susceptibility loci. At least two other haplotype blocks within the 20q12-q13.1 genomic region show evidence of association with type 2 diabetes. Additional genotyping and genetic analysis will be carried out in an effort to confirm that these haplotype blocks contain type 2 diabetes susceptibility genes. These studies will consist of high density SNP genotyping to clearly define the associated haplotype blocks and expansion of the analysis to other populations to try to confirm association to type 2 diabetes and assess association with metabolic phenotypes (e.g. insulin resistance, (3-cell function, etc.). Confirmation of association in multiple populations will justify a more detailed molecular genetic analysis similar to that being proposed for PTPN1.
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