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 linkage of T2DM with the same region has been replicated in several and diverse Caucasian and Chinese populations. Our strategy to search for the underlying diabetes susceptibility gene(s) has been based on using 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. The 1q21-q23 area has a high gene content and so far, over 80 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 between most 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 a 13 Mb interval spanning the linkage peak in most populations. So far we received the genotyping results about half of the markers, which are currently being evaluated. We expect to receive the genetypes for the remaining half of the SNPs within a few weeks. This will provide us with approximately 2500 SNPs (including over 500 SNPs that were genotyped here in Phoenix), giving an average density of one SNP per every 5.2 kb. We anticipate that the results obtained with these SNPs will direct our focus to 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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