In an earlier genome-wide linkage scan for genes predisposing to type 2 diabetes mellitus (T2DM) in the Pima Indians, we obtained the strongest evidence for linkage with markers on chromosome 1q21-q23. Subsequently, the same region has been linked with T2DM in several Caucasian populations and a Chinese population. Our strategy to search for the underlying diabetes susceptibility gene(s) involves two complementary approaches: 1) systematic analysis of densely spaced single nucleotide polymorphisms (SNPs); and 2) investigation of plausible candidate genes within the linked region for variants/mutations. The 1q21-q23 area has a very high gene content and so far, close to 60 candidate genes have been/are being analyzed. Informative SNPs are tested for association with diabetes, and their effect on the linkage is also evaluated. So far, we identified a few markers that are nominally associated with T2DM, but none could explain the linkage. Currently we are continuing with the analysis of candidate genes in a systematic way, starting from the peak of linkage and moving in both (centromeric and telomeric) directs. Based on our in-house simulations performed by Dr. Robert Hanson, we need to achieve a very high SNP density (5-10 kb) to efficiently search for the susceptibility gene(s). Currently, we are analyzing markers at ever 25 kb, and we expect that the combined analytical strategy involving evenly spaced SNPs plus detailed investigation of candidate genes will help to define the critical interval harboring the T2DM susceptibility locus and lead to the identification of the underlying mutation(s).
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