We have preliminary data that essentially all monozygotic twins of patients with type 1A diabetes eventuallydevelop persistent anti-islet autoantibody expression, that a major subset, but not all such twins eventuallyprogress to diabetes, and that a specific subgroup of siblings (HLA DR3-DQ2/DR4-DQ8 who share both HLAhaplotypes with their sibling proband, but not if they share one, despite identical DR and DQ alleles) have arisk of islet autoimmunity as high as ever reported for monozygotic twins. This suggests that there is a majorgene X, in linkage with DR and DQ that contributes to extreme risk of islet autoimmunity, and that subgroupsof twins are likely to have different diabetes risk relative to age of progression. We propose in collaborationwith TrialNet to develop a twin resource with genetically characterized and prospectively followed discordantmonozygotic and dizygotic twins of patients with type 1A diabetes and non-twin siblings from the samefamilies. Life Table projected risk of progression to expression of persistent anti-islet autoantibodies as wellas diabetes will be assessed relative to known genetic polymorphisms for groups of discordant twins, andthe twins will be compared to their similarly characterized non-twin siblings. We hypothesize that DR3-DQ2/DR4-DQ8 monozygotic twins, will have an extremely high risk and early time course of activating antiisletautoimmunity not different from siblings with DR3-DQ2/DR4-DQ8 who share both HLA haplotypes withtheir sibling proband, while dizygotic twins will not differ from HLA matched siblings of patients with a muchlower risk.
The specific aims of the project are: 1. Assemble and characterize the largest current series oftype 1 diabetes discordant monozygotic and dizygotic twins. 2. Determine point estimate anti-isletautoantibodies. 3. Begin prospective follow-up of twins in relation to expression of islet autoimmunity anddiabetes to compare with their non-twin siblings and siblings from TrialNet and DAISY. 4. Perform highdensity MHC+ SNP mapping in DZT and non-twin siblings from these families to identify the MHC-linkedgene(s) responsible for the increased risk for islet cell autoimmunity in DR3-DQ2/DR4-DQ8 siblings whoshare both haplotypes with the affected family proband.
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