Type 1A Diabetes: Expanding Limits Genetic Prediction

我们有初步的数据，基本上所有的1A型糖尿病患者的单卵双胞胎最终 发展持续的抗胰岛自身抗体表达，这是一个主要的子集，但不是所有这样的双胞胎最终 糖尿病的进展，以及一个特定的兄弟姐妹亚组（HLA DR 3-DQ 2/DR 4-DQ 8， 单倍型与他们的兄弟先证者，但如果他们共享一个，尽管相同的DR和DQ等位基因）有一个 胰岛自身免疫的风险与单卵双胞胎一样高。这表明，有一个主要的 与DR和DQ相关的X基因，导致胰岛自身免疫的极端风险， 的双胞胎可能有不同的糖尿病风险相对于年龄的进展。我们合作提议 与TrialNet一起开发了一种具有遗传特征和前瞻性跟踪的不一致性的孪生资源， 1A型糖尿病患者的同卵双胞胎和异卵双胞胎以及来自同一人群的非双胞胎兄弟姐妹 家庭生命表也预测了持续性抗胰岛自身抗体表达的进展风险 因为糖尿病将相对于不一致双胞胎组的已知遗传多态性进行评估， 将双胞胎与其具有相似特征的非双胞胎兄弟姐妹进行比较。我们假设DR 3- DQ 2/DR 4-DQ 8单卵双胞胎，将具有极高的风险和早期激活抗胰岛 自身免疫性与DR 3-DQ 2/DR 4-DQ 8兄弟姐妹没有不同，他们与 他们的兄弟姐妹先证者，而双卵双胞胎将没有什么不同，从HLA匹配的兄弟姐妹的患者有很多 降低风险。该项目的具体目标是：1。组装并表征当前最大的 1型糖尿病单卵双胞胎和双卵双胞胎不一致。2.确定点估计反胰岛 自身抗体3.开始前瞻性随访双胞胎的胰岛自身免疫表达， 糖尿病与他们的非双胞胎兄弟姐妹和来自TrialNet和DAISY的兄弟姐妹进行比较。4.执行高 DZT和来自这些家族的非双胞胎兄弟姐妹中的密度MHC+ SNP作图，以鉴定MHC连锁的 在DR 3-DQ 2/DR 4-DQ 8同胞中， 与受影响的家族先证者共享两种单倍型。

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