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

华盛顿糖尿病评估 (DEW-IT) 临床中心*

• 批准号: 6710181
• 负责人: William A. Hagopian
• 金额: $ 100万
• 依托单位: PACIFIC NORTHWEST RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6710181
• 关键词: Diabetes; Evaluation; Washington; DEW; Clinical

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.

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两方面的影响，其影响程度大致相同。大量合作安排汇集了许多患者样本，有助于鉴定几种致病基因多态。确定环境因素变得更加困难，但也应该受益于合作的方法。华盛顿糖尿病评估(Dew-IT)研究是一项基于3.2万名受试者的人群筛查计划，将识别6000多名患有未来糖尿病遗传风险的幼儿。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能力，以确定共同的环境触发因素。 我们建议跟踪高遗传风险受试者(Dew-IT家族和Dew-IT普通队列)经历三个假定的疾病阶段：a)血清转换为单一抗体阳性到GAD、ICA512/IA2和胰岛素之一，b)从一种确定的自身抗体进展到多种确定的自身抗体，以及c)低β细胞功能的发展(空腹C肽)或临床糖尿病。一级亲属将在所有阶段按顺序接受跟踪，但b)和c)阶段将在密集的环境采样之前，由来自一般Dew-IT队列的抗体阳性的遗传高危儿童来扩大。频繁的患者样本将包括血清、PBMC、咽拭子、头发、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、疾病和其他压力源。环境采样还将包括在患者日记中确定的选定食品。基因分型将包括人类白细胞抗原DR-DQ和其他10个已知的糖尿病风险基因座，以及其他10个基因座，这些基因座旨在检测已知可减轻毒性暴露的β细胞基因的多态性。 包括父母双方在内的三人将被收集用于TDT分析。测量的环境暴露包括肠道病毒、膳食真菌毒素、疾控中心选择的环境毒素和其他地点建议的暴露。疾病进展将根据基因效应、环境效应和消失的环境效应进行分析。疾病分期、样本收集和分析以及统计方法将遵循该联盟制定的共识方法。总体目标是确定启动和/或传播儿童自身免疫性糖尿病发病机制的环境因素。