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.
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