The investigators have now completed a genome scan on the genotyping set of the San Antonio Family Diabetes Study (SAFADS) population which consists of 444 individuals from 27 extended pedigrees ascertained on a low income, Mexican American proband with type 2 diabetes. Multipoint variance components linkage analysis revealed strong evidence for linkage between a region on chromosome 10q25.3-26.1 and the trait type 2 diabetes (LOD = 2.88, p = 0.00014) and age of diabetes onset (LOD = 3.75, p = 1.6x10-6). The investigators now propose to perform genetic disequilibrium mapping of the 10 cM region centered on the marker D10S587 which is the point of maximum signal. A number of publicly available SNPs have been mapped, but preliminary analysis of five of these suggested that they were uninformative in the investigators' Mexican American population. However, single strand conformational polymorphism (SSCP) analysis of these five and an additional 13 efficiently revealed either known variants or identified new polymorphisms. They therefore propose to develop up to 150 new SNPs from known SNP and EST clones mapped to the 10q25.3-26.1 region for their linkage disequilibrium mapping project. All 444 SAFADS participants in the genotyping set will then be typed for each SNP. Once a region is determined to harbor a diabetes susceptibility gene, a BAC contig spanning the region of highest genetic linkage disequilibrium will be constructed and DNA sequenced to identify open reading frames. Approximately 50 additional SNPs will be generated from the diabetes candidate genes which are identified, and these will be tested in SAFADS families. Disequilibrium mapping will be performed by joint linkage/association analyses using 1) the multipoint variance components approach and 2) the gamete competition model. They will also employ a novel statistical functional genomics approach to localizing functional variants and polymorphisms exhibiting the highest disequilibria with the putative susceptibility loci.
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