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 analysis of densely spaced single nucleotide polymorphisms (SNPs) in affected an unaffected Pimas for associations with the disease. The marker approach consists of two complementary parts: 1) systematic analysis of densely spaced SNPs (on average less than 50 kilobases apart); and 2) investigation of plausible candidate genes within the linked region for variants. The 1q21-q23 area has a very high gene content and so far, close to 40 candidate genes have been/are being analyzed. Informative SNPs are tested for association with diabetes either individually or combined into haplotypes, 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. Based on our in-house simulations performed by Dr. Robert Hanson and empirical evidence, it has become obvious that a much higher SNP density must be achieved for an efficient search for the diabetes susceptibility gene(s). 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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