Celiac disease is a severe and chronic gastrointestinal disorder in which immune-mediated damage to the small intestine leads to malabsorption. It is triggered by ingestion of specific grain proteins in genetically susceptible individuals. It is well established that a gene or genes in the HLA region is an important risk factor for the disease, being necessary but not sufficient for the development of celiac disease. Segregation analyses have been shown that at least one other gene is involved, which is not linked to HLA and is, in fact, a stronger determinant of familial segregation. The objective of the proposed study is to locate the non-HLA linked gene(s) contributing to disease susceptibility. Linkage analysis of multicase families will be used to locate the non-HLA-linked susceptibility gene(s). Model-free affected sib pair and other related pair methods of linkage analysis will be used. Approximately 350 highly polymorphic microsatellite DNA markers will be studied to localize disease susceptibility genes. Following the application of model-free nonparametric methods, more traditional model-based maximum likelihood linkage analysis of three generation pedigrees will be used to corroborate the results. The highest prevalence of celiac disease is in the West of Ireland. The study will use DNA and Epstein-Barr virus-transformed cell lines, previously collected by the investigators from a large cohorts of celiac patients, family members, and control subjects in the West of Ireland. Additional DNA samples will be provided by collaborators in Galway, Ireland. These studies will elucidate the genetic etiology of celiac disease, an immune-mediated disorder with a known eliciting antigen and partially defined genetic basis. This serious illness, which few American investigators have had an opportunity to study, is an excellent paradigm for HLA-associated, immune-mediated disorders.
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