Candidate gene regions and genetic heterogeneity in gluten sensitivity

Background-Gluten sensitivity is a common multifactorial disorder, manifest ed in the small intestine or on the skin as typical coeliac disease or derm atitis herpetiformis, respectively. The only established genetic risk facto r is HLA DQ2. Aims-We tested genetic Linkage of previously reported chromosomal loci 5q a nd 11q in Finnish families with gluten sensitivity. We also tested if genet ic linkage to candidate loci on 5q, 11q, 2q33, and HLA DQ differed with res pect to clinical manifestations or sex. Subjects-We studied 102 Finnish families with affected sibpairs. For hetero geneity analysis, families were divided into subgroups according to sex and the presence of dermatitis herpetiformis, the skin manifestation of gluten sensitivity. Methods-Non-parametric linkage between microsatellite markers and disease w as tested. Linkage heterogeneity between subgroups was tested using the M t est. The transmission/disequilibrium test and association analysis were per formed. Results-Evidence of linkage to 11q (MLS 1.37),but not to 5q, was found in t he entire dataset of 102 families. Heterogeneity between subgroups was sugg ested: families with only the intestinal disease showed linkage mainly to 2 q33 whereas families with dermatitis herpetiformis showed linkage to 11q an d 5q, but not to 2q33. Linkage in all three non-HLA loci was strongest in f amilies with predominantly male patients. HLA DQ2 conferred much stronger s usceptibility to females than males. Conclusions-Independent evidence for the suggested genetic linkage between 11q and gluten sensitivity was obtained. The possible linkage heterogeneity suggests genetic differences between intestinal and skin manifestations, a nd the gender dependent effect of HLA DQ2.