Celiac disease (CD) is a major public health problem affecting up to 1% of the general population and leading to significant morbidity and mortality. In the U.S., CD is still under-diagnosed due to low awareness and lack of a comprehensive screening program in high-risk groups. Our unique large prospective study of children at high-risk of CD (R01 DK50979, 9/1995-11/2006, M. Rewers, P.I.) has responded to many of the research priorities identified by the 2004 NIH Consensus Development Conference on Celiac Disease (1). This competing renewal application proposes to take to a new level characterization of genetic determinants of variable CD phenotypes to develop optimal approaches to screening, follow-up and prevention of CD. The proposed study aims to: [unreadable] [unreadable] SPECIFIC AIMS: [unreadable] 1. Determine the incidence and the natural history of celiac disease in children aged 10-15, by prospective annual testing for TG IgA autoantibodies and follow-up intestinal biopsy in positive subjects identified in already established cohorts: [unreadable] 1.1. General population children with high risk HLA-DR,DQ genotypes (n=1,346) [unreadable] 1.2. Type 1 diabetic (T1D) children (n=2,800) [unreadable] 1.3. Non-diabetic first degree relatives of T1D patients (n=1,065) [unreadable] [unreadable] 2. Answer a fundamental question whether there are genetic polymorphisms other than the HLA-DQ alleles,within or outside the MHC region that confer major risk for CD, in [unreadable] 2.1. Nested case-control association studies of candidate genetic markers. [unreadable] 2.2. Family-based multi-SNP analyses of MHC haplotypes associated with celiac disease and T1D. [unreadable] [unreadable] 3. In a nested case-control study using novel markers, e.g., zonulin, Glb1 autoantibodies, characterize [unreadable] determinants of apparent window of susceptibility to dietary gluten. [unreadable] [unreadable] 4. Assess the impact of seropositivity for TG IgA on intestinal mucosa morphology, intestinal permeability,growth and development, bone mineralization and micronutrient deficiencies in screening detected children with and without T1D. [unreadable] [unreadable] [unreadable]