In a previous genome-wide linkage scan to screen for type 2 diabetes genes in the Pima Indians, the highest LOD score (2.4) was obtained with marker D1S1677 on chromosome 1q. Recently, the same region was linked with type 2 diabetes in Caucasians. To further refine this segment carrying the putative diabetes susceptibility locus, we have been evaluating densely spaced single nucleotide polymorphisms (SNPs) by association analysis in selected affected an unaffected Pimas. After an inital analysis of 40 SNPs identified with the use of a YAC conting encompassing D1S1677, we are now in the process of establishing a dense map of physically ordered markers defined by sequencing of BAC clones covering this region. Our goal is to establish the degree of linkage disequilibrium across this interval, followed by systematic analyses of SNPs at the desired distances. In addition to conventional methods for identification of appropriate SNPs (e.g. exploring sequences from BAC ends), we are also utilizing an Amplified Fragment Length Polymoprhism (AFLP)-based capture as described in project Z01-DK69074. The identified new SNPs will be analyzed for association with diabetes either individually or combined into haplotypes. We expect that this strategy will define a critical interval harboring the susceptibility locus and help in the selection of positional candidate genes for mutation screening in diabetic subjects. - Pima Indians, type 2 diabetes, linkage on 1q21-q23, positional cloning - Human Subjects
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