This is the first resubmission of a proposal for four years of support to map non-HLA-linked loci for gluten sensitive enteropathy (GSE) using affected sibling pair families. GSE is a histological abnormality of the jejunum which improves on withdrawal of gluten from the diet, and includes both patients with the malabsorption disorder celiac disease (CD) and those with the gluten sensitive skin disorder dermatitis herpetiformis (DH). Patients with CD have symptoms including growth failure, abdominal pain, and diarrhea. The risk to first degree relatives of an individual with GSE is 8-12% and the risk for MZ twins is 70%. GSE has a strong association with HLA DQ genotypes. However, HLA alone is not sufficient to explain the hereditary nature of GSE. The applicants propose to: (1) ascertain 100 kindreds with at least two affected siblings; (2) collect blood samples from the affected siblings, their parents, additional affected family members, and connecting family members; (3) confirm diagnoses through biopsy reports; (4) perform DNA-based HLA typing of DQA, DQB, and DQCAR (in between DQA and DQB) loci and assess the degree of association with individual loci and haplotypes at these loci; (5) test for linkage with a dozen candidate genes and regions suggested by the clinical correlations of GSE with various diseases and by tentative immunopathogenesis; and (6) perform a genome search with 250 primarily tri- and tetranucleotide repeat markers (intermarker distances < 20 cM, average heterozygosity >76%) on up to 400 individuals if none of the candidate genes show linkage to GSE.
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