Celiac disease (CD) is a major but under-diagnosed public health problem affecting 0.4-1 percent of the general U.S. Large prospective studies of high-risk children are needed to characterize genetic and environmental determinants of variable CD phenotypes and to develop optimal screening and prevention strategies. CD offers a model of the interplay between genetic, immunologic, and environmental factors in the etiology of autoimmune diseases. Genetic susceptibility to CD is largely restricted to the HLA- DR3,DQ2 and DR4,DQ8 haplotypes. Autoantibodies to tissue transglutaminase (TG) are the best serological marker of CD, however, reliable assays for other CD-specific autoantibodies and epitope characterization could greatly improve our ability to predict and stage CD. In contrast to most human autoimmune diseases, the critical antigen triggering CD is known. Elimination of dietary gliadin resolves the symptoms and prevents long-term complications, offering hope that other autoimmune diseases can be prevented or treated by modification of environmental factors. The proposed study will use three population-based cohorts of children at high risk of CD, with a large number of patients already positive for TG autoantibodies, that are available in our center in Denver to: 1. Determine the incidence, environmental and genetic determinants, and the natural history of celiac disease through a prospective follow-up of three cohorts of high-risk children: a) Type 1 diabetic children (n=1,361), aged 0-18 years, examined annually; b) Non-diabetic first degree relatives of patients with type 1 diabetes (n=929), aged 0-18 years, examined annually; c) General population infants with high risk HLA-DR3/3, 3/4 or 3/x genotypes (n=1016) and those with lower risk HLA-DR4/x and 4/4 genotypes (n=581) examined at ages 9, 15, 24 months, and yearly thereafter; 2. Characterize TG epitope specificity in terms of their cross- sectional relationship to small bowel biopsy results and prospective relationship to disease progression. 3. Assess the clinical impact of seropositivity for TG IgA in screening detected cases on intestinal mucosa morphology, intestinal permeability, growth and development, bone mineralization and micronutrient deficiencies.
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