Type 1A Diabetes: Expanding Limits Genetic Prediction

University Of Colorado Denver, Aurora CO

Investigators

Linked publications & trials

Abstract

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