An autosomal screen for genes that predispose to celiac disease in the western counties of Ireland

Celiac disease is a strongly heritable gastrointestinal illness that is an especially important model of the genetically complex multifactorial immune mediated diseases. The HLA component of celiac disease (a specific HLA-DQ heterodimer)is largely established and is relatively uncomplicated, and the environmental component (gluten and related grain storage proteins in the diet) is remarkably well understood. Previous family studies of celiac disease suggested that there is at least one important non-HLA locus. This locus may be a stronger genetic factor than HLA, and it apparently has a recessive mode of inheritance. We used a three step genome screening protocol to identify loci that contribute to celiac disease in the western counties of ireland, a region with the highest prevalence of celiac disease in the world. The most significant of several possible non-HLA loci that we found was on chromosome 6p about 30 cM telomeric from HLA. It has a multipoint maximum lod score of 4.66 (compared with 4.44 for HLA-DQ) and appears to have a recessive mode of inheritance. Our study localizes and provides strong evidence for linkage of at least one non-HLA locus to celiac disease and may serve as a prototype for an efficient approach to screening the human genome for loci that contribute to complex diseases.