Type 1A Diabetes: Expanding Limits Genetic Prediction

1A 型糖尿病：扩大遗传预测的限制

• 批准号: 7938963
• 负责人: GEORGE S EISENBARTH
• 金额: $ 28.28万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7938963
• 关键词: Affect; Age; Alleles; Autoantibodies; Autoimmune Process; Autoimmunity; Collaborations; Complex; Data; Diabetes Mellitus; Dizygotic Twins; Family; General Population; Genes; Genetic; Genetic Polymorphism; Haplotypes; Insulin-Dependent Diabetes Mellitus; International; Islet Cell; Life Tables; Link; Major Histocompatibility Complex; Monozygotic Twinning; Monozygotic twins; Natural History; Patients; Relative (related person); Reporting; Research Institute; Resources; Risk; Series; Siblings; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; Subgroup; TNFRSF10A gene; Technology; Time; Twin Multiple Birth; cooperative study; density; diabetes risk; follow-up; high risk; islet; molecular array; proband; prospective

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.

我们有初步数据表明，基本上所有 1A 型糖尿病患者的同卵双胞胎最终都会 发展出持续的抗胰岛自身抗体表达，这是一个主要子集，但最终并非所有此类双胞胎 进展为糖尿病，并且兄弟姐妹的特定亚组（HLA DR3-DQ2/DR4-DQ8 共享 HLA 与其兄弟先证者的单倍型，但如果他们共享一个，尽管具有相同的 DR 和 DQ 等位基因，则不会）具有 同卵双胞胎患胰岛自身免疫的风险与以往报道的一样高。这表明存在一个重大的 基因 X，与 DR 和 DQ 相关，导致胰岛自身免疫的极端风险，并且该亚组 相对于进展年龄，双胞胎的糖尿病风险可能不同。我们建议合作 与 TrialNet 合作开发具有遗传特征和前瞻性跟踪不一致的双胞胎资源 1A 型糖尿病患者的同卵双胞胎和异卵双胞胎以及同一兄弟姐妹的非双胞胎兄弟姐妹 家庭。生命表还预测了持续抗胰岛自身抗体表达进展的风险 因为将根据不一致双胞胎群体的已知遗传多态性来评估糖尿病，并且 这对双胞胎将与具有相似特征的非双胞胎兄弟姐妹进行比较。我们假设 DR3- DQ2/DR4-DQ8 同卵双胞胎，激活抗胰岛细胞的风险极高且时间较早 自身免疫与 DR3-DQ2/DR4-DQ8 的兄弟姐妹没有什么不同，他们与 DR3-DQ2/DR4-DQ8 共享两种 HLA 单倍型 他们的先证者兄弟姐妹，而异卵双胞胎与 HLA 匹配的患者的兄弟姐妹没有什么不同。 风险较低。该项目的具体目标是： 1. 组装并表征当前最大的系列 1 型糖尿病不一致的同卵双胞胎和异卵双胞胎。 2. 确定抗胰岛点估计 自身抗体。 3. 开始对双胞胎进行与胰岛自身免疫表达相关的前瞻性随访 与他们的非双胞胎兄弟姐妹以及来自 TrialNet 和 DAISY 的兄弟姐妹进行比较。 4. 表现出色 对 DZT 和来自这些家庭的非双胞胎兄弟姐妹进行密度 MHC+ SNP 定位，以识别 MHC 相关的 导致 DR3-DQ2/DR4-DQ8 兄弟姐妹胰岛细胞自身免疫风险增加的基因 与受影响的家族先证者共享两种单倍型。