Type 1 diabetes (T1D) arises from the autoimmune destruction of the insulin-secreting beta cells of the pancreas resulting in a complete dependence on exogenously administered insulin for survival. Although there is ample evidence from twin studies that some portion of susceptibility to T1D is genetically determined, within families the disorder follows no clear mode of inheritance and is generally thought to result from the combined effects of multiple genes interacting with non-genetic factors. The goal of our proposed study is to identify genes that contribute to susceptibility to T1D. Genome-wide scans have implicated more than 20 additional chromosomal locations as susceptibility loci but with the exception of the HLA region on 6p (IDDM1) and the insulin gene (INS) region on 11p (IDDM2), there has been little agreement between studies. We have recently completed a new linkage analysis in T1D with significantly greater power than previous studies. Our combined sample of 767 families (831 ASPs), provides 90 percent power to detect linkage for loci with lambdas greater than or equal to 1.3 at P = 7.4 x 10-4. Three chromosomal regions with significant evidence of linkage (P less than 2.2 x 10-5; lod scores greater than 4), 6p21 (IDDM1), 11p15 (IDDM2) and 16q22-24, were identified and four more with suggestive evidence (P less than or equal to 7.4 x 10-4, lod scores greater than or equal to 2.2), 10p11 (IDDM10), 2q31 (IDDM7/12/13), 6q21 (IDDM15) and 1q42. We propose a stepwise approach in 3 aims to isolate putative disease loci from these sites starting with the region at 16q22-24 where the evidence for linkage attains a genome-wide level of significance (lod = 4.13). In the first aim, we will maximize the number of informative meioses we have in the region by genotyping all of our available multiplex families with a dense map of microsatellite markers. Incidental to this effort, we will test these markers for evidence of allelic association with T1D.
In aim number 2 the focus will be on detecting association with T1D and we will use sample pooling to facilitate the genotyping of a large number of closely spaced SNP markers within our candidate region following up interesting results by TDT. Once we have completed a comprehensive screen of the region and identified markers in our panel that show association with T1D, we will proceed to aim number 3 in which the haplotype structure of the region surrounding the associated marker(s) will be determined. Transmission of single marker alleles and haplotypes of markers in the region will be assayed in families, risk haplotype(s) will be defined, SNPs with alleles specific to the risk haplotype(s) will be identified and genes containing such SNPs will be studied with functional assays.
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