Type 1A Diabetes: Expanding Limits Genetic Prediction

1A 型糖尿病：扩大遗传预测的限制

• 批准号: 7686452
• 负责人: GEORGE S EISENBARTH
• 金额: $ 47.57万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686452
• 关键词: Affect; Age; Alleles; Autoantibodies; Autoimmunity; Class; Collaborations; Complex; Data; Diabetes Mellitus; Dizygotic Twins; Family; General Population; Genes; Genetic; Genetic Polymorphism; Haplotypes; Insulin-Dependent Diabetes Mellitus; International; Islet Cell; Islets of Langerhans; Life Tables; Link; Major Histocompatibility Complex; Monozygotic Twinning; Monozygotic twins; Natural History; Patients; Relative (related person); Relative Risks; Reporting; Resources; Risk; Series; Siblings; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; Subgroup; TNFRSF10A gene; Technology; Time; Twin Multiple Birth; density; diabetes risk; follow-up; 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，基本上所有1A型糖尿病患者的同卵双胞胎最终都是 形成持久的抗胰岛自身抗体表达，这是一个主要的亚群，但最终不是所有这样的双胞胎 进展为糖尿病，并且兄弟姐妹的一个特定亚群(具有两个共同的HLA的HLADR3-DQ2/DR4-DQ8) 单倍型与他们的兄弟先证者，但如果他们共享一个，尽管DR和DQ等位基因相同，但不会)有一个 胰岛自身免疫的风险与以往报道的同卵双胞胎一样高。这表明有一个重大的 X基因，与DR和DQ连锁，导致胰岛自身免疫的极端风险，以及该亚群 的双胞胎患糖尿病的风险可能与进展年龄有关。我们在合作中提出 与TrialNet合作开发具有遗传特征和预期遵循不一致性的双胞胎资源 1A型糖尿病患者的同卵和异卵双胞胎及其非双胞胎兄弟姐妹 家人。寿命表预测进展为持续抗胰岛自身抗体表达的风险 由于糖尿病将根据已知的不和谐双胞胎群体的基因多态进行评估，以及 这对双胞胎将与他们性格相似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，将有极高的风险和早期激活胰岛的时间过程 自身免疫与携带DR3-DQ2/DR4-DQ8的兄弟姐妹没有区别，后者具有两种单倍型 他们的兄弟姐妹先证者，虽然异卵双胞胎不会与许多患者的HLA相合兄弟姐妹不同 风险更低。该项目的具体目标是：1.组装和表征目前最大的 1型糖尿病不协调的同卵和异卵双胞胎。2.确定点估计抗胰岛 自身抗体。3.开始对双胞胎进行与胰岛自身免疫表达有关的前瞻性随访 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.发挥高水平 DZT及其非双胞胎同胞的密度MHC+SNP定位以鉴定MHC连锁 DR3-DQ2/DR4-DQ8同胞中胰岛细胞自身免疫风险增加的基因(S) 与受影响的先证者共享这两种单倍型。