Celiac disease (or gluten sensitive enteropathy) is a debilitating gastrointestinal disorder in which an aberrant immune response to dietary gluten results in destruction of the jejunal mucosa. Celiac disease is one of at least nine immune mediated disorders associated with the histocompatibility antigens HLA-B8 and HLA-DR3. Recently, many investigators including ourselves have described alterations of immunity in subjects with the HLA-B8/DR3 haplotype, which may underlie the predisposition to immune mediated illnesses associated with this haplotype. The proposed study will investigate the altered immunity associated with HLA-B8/DR3 as a risk factor for the development of celiac disease. A large cohort of patients and their families in the West of Ireland will be studied with regard to several immune parameters previously found to be associated with the HLA-B8/DR3 haplotype, serologically detected alleles of the HLA A, B and C loci, and DNA polymorphisms representing alleles of the HLA-DR, DQ and DP loci. The first objective will involve a family study to test, by segregation and linkage analysis, the hypothesis that detection of these immune abnormalities may allow identification of individuals heterozygous for a gene in the HLA region which, in double dose, predisposes to celiac disease; i.e., detection of """"""""carriers"""""""". Pedigree discriminant analysis of the multivariate data on each member of the pedigrees will be used to define a constellation of immune parameters that segregates as a single gene. A second objective will be accomplished by a case-control study designed to test two alternative hypotheses, namely: a) that these immune abnormalities will be more strongly associated with celiac disease than will specific HLA alleles, or b) that the immune abnormality trait reflects the action of a second gene which is required in addition to specific HLA class II alleles for the development of celiac disease. The case-control study will be used to determine the clinical significance of the immune abnormality trait as defined by the segregation study. The strength of the population associations between celiac disease and specific HLA alleles or the immune abnormality trait will be measured by estimating a statistical index which has been called the population attributable risk or etiologic fraction. The results of these studies may help elucidate the genetic basis of celiac disease, and will clarify the clinical significance of immune abnormalities attributed to genes in the HLA region.
