In a previous 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 1q linkage of T2DM has been replicated in several, diverse populations. Our strategy to search for the underlying diabetes susceptibility gene(s) has been based on two complementary approaches: 1) systematic analysis of densely spaced single nucleotide polymorphisms (SNPs); and 2) investigation of candidate genes within the linked region for variants/mutations. So far, over 100 candidate genes have been/are being analyzed by sequencing in a subset of diabetic and non-diabetic Pimas. Informative SNPs are tested for association with diabetes, and their effect on the linkage is also evaluated. More recently, an international collaborative Chromosome 1 Consortium has been established by uniting several of the groups which detected T2DM linkage on 1q, with the goal to facilitate search for the underlying diabetes gene(s). This startegy involves analysis of over 5000 subjects from five populations (including about 1000 Pimas), and so far this effort has led to genotyping of over 2000 SNPs within an initial interval of 13 Mb spanning the linkage peak in most populations. We found a few areas showing nominal association with T2DM and so far analyzed extensively a ~200 kilobase region in which multiple SNPs showed the strongest association with the disesase, and also could explain about 25% of the original linkage. Although we detected numerous variants, this strategy did not help to identify the putative causative variant. This area is fairly conserved between human and other species, and therefore an experimental animal model (such as knockout mice) may be needed to assess the functional relevance of the variants in this region. As the 13 Mb region may not include the causative mutation (the whole linked region is over 30 Mb long), more SNPs has been (or are being) genotyped to expand the analyzed region. We just received an additional 1000 SNPs genotyped by the Consortium and their analysis is in progress. This will provide us with approximately 3500 SNPs (including over 500 SNPs that were genotyped here in Phoenix), giving a density range of one SNP per every 5-25 kb. We anticipate that the results obtained with these SNPs will help to prioritize region(s) which are likely to harbor the diabetes gene(s), and will narrow down the area of interest for further thorough molecular genetic analysis.
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