Diabetes Evaluation in Washington (DEW-IT) Clinical Cen*

描述（由申请人提供）： 1型（自身免疫性）糖尿病的病因涉及遗传和环境的影响，其影响程度大致相等。汇集许多患者样本的大型合作安排有助于确定几种致病遗传多态性。环境因素的确定比较困难，但也应受益于合作办法。华盛顿糖尿病评估（DEW-IT）研究是一项基于32，000名受试者人群的筛查计划，将确定6，000多名未来糖尿病遗传风险升高的幼儿。将受试者群体与美国和其他地方类似规模的基于人群的筛查研究相结合，应该可以实现足够的样本量和统计功效，以确定常见的环境触发因素。 我们建议通过三个假定的疾病阶段对高遗传风险受试者（DEW-IT家族和DEW-IT一般队列）进行随访：a）血清转化为GAD、ICA 512/IA 2和胰岛素之一的单一抗体阳性，B）从一种定义的自身抗体进展为多种定义的自身抗体，以及c）发展为低β细胞功能（空腹C肽）或临床糖尿病。一级亲属将在所有阶段按顺序进行随访，但在密集环境采样之前，阶段B）和c）将通过来自一般DEW-IT队列的抗体阳性遗传风险儿童进行扩增。频繁的患者采样将包括血清、PBMC、咽拭子、毛发、尿液和粪便。我们还将调查儿童的食物摄入量、疫苗接种、过敏、疾病和其他压力因素。环境采样还将包括患者日记中确定的选定食品。基因分型将包括HLA DR-DQ和10个其他已知的糖尿病风险基因座，以及10个其他基因座，旨在检测已知可减轻毒性暴露的β细胞基因多态性。 将收集三人组（包括父母双方）进行TDT分析。测量的环境暴露包括肠道病毒、饮食真菌毒素、CDC选择的环境毒素和其他地点提出的暴露。疾病进展将从基因效应、环境效应和基因与环境效应方面进行分析。疾病分期、样本收集和分析以及统计方法将遵循联盟制定的共识方法。总体目标是确定环境因素启动和/或传播的儿童自身免疫性糖尿病的发病机制。

DESCRIPTION (provided by applicant): The etiology of Type 1 (autoimmune) diabetes involves both genetic and environmental influences of roughly equal magnitude. Large cooperative arrangements pooling many patient samples have aided in identification of several of the causative genetic polymorphisms. Identification of environmental factors has been more difficult, but should also benefit from a cooperative approach. The Diabetes Evaluation in Washington (DEW-IT) study is a 32,000 subject population-based screening program, which will identify more than 6,000 young children at elevated genetic risk of future diabetes. Combining subject groups with similarly sized population-based screening studies in the US and elsewhere should make it possible to achieve sufficient sample sizes and statistical power to identify common environmental triggers. We propose to follow subjects at high genetic risk (DEW-IT family and DEW-IT general cohorts) through three putative disease stages: a) seroconversion to single antibody positivity to one of GAD, ICA512/IA2, and insulin, b) progression from one to multiple defined autoantibodies, and c) development of low beta cell function (fasting C-peptide) or clinical diabetes. First degree relatives will be followed sequentially through all stages, but stages b) and c) will be augmented by antibody-positive genetically-at-risk children from the general DEW-IT cohort, prior to intense environmental sampling. Frequent patient sampling will include serum, PBMC, throat swabs, hair, urine and stool. We will also survey children on food intake, vaccinations, allergies, illnesses and other stressors. Environmental sampling will also include selected foodstuffs identified in patient diaries. Genotyping will include HLA DR-DQ and 10 other known diabetes risk loci, as well as 10 other loci designed to detect polymorphisms at beta cell genes known to mitigate toxic exposures. Trios, including both parents, will be collected for TDT analyses. Measured environmental exposures include enteroviruses, dietary mycotoxins, environmental toxins selected by the CDC, and exposures proposed by other sites. Disease progression will be analyzed with respect to gene effects, environmental effects, and gone x environment effects. Disease staging, sample collection and analyses, and statistical approach will follow the consensus approach developed by the consortium. The overall goal is to identify environmental factors initiating and/or propagating the pathogenesis of childhood autoimmune diabetes.