In our previous genome-wide linkage scan to screen for type 2 diabetes genes in the Pima Indians, the highest LOD score was obtained with marker D1S1677 on chromosome 1q. Since then, the same region was linked with type 2 diabetes in three different studies of Caucasians. Our strategy to search for the underlying diabetes susceptibility gene involves analysis of densely spaced single nucleotide polymorphisms (SNPs) in selected affected an unaffected Pimas for associations with the disease. We are assembling a set of overlapping bacterial artificial chromosome (BAC) clones that represent human genomic DNA from this region. The ends on these clones are tested for the presence of SNPs, thus providing an ordered array of markers. Furthermore, we are investigating selected candidate genes positioned within this region. So far, over 20 candidate genes were/are analyzed, and we have performed analysis of approximately 80 SNPs in the interval of linkage. Informative SNPs are analyzed for association with diabetes either individually or combined into haplotypes, and their effect on the linkage is also evaluated. We identified several markers to be significantly associated with diabetes, but none could explain the linkage. We noticed that the degree of linkage disequilibrium between the analyzed markers extends only over a short physical distance, and therefore a much higher SNP density must be achieved for an efficient search for the diabetes susceptibility gene. We expect that this strategy will help to define the critical interval harboring the susceptibility locus that will aid in the selection of positional candidate genes for mutation screening in diabetic subjects.
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