The CTLA4/CD28 gene region on chromosome 2q33 confers susceptibility to celiac disease in a way possibly distinct from that of type 1 diabetes and other chronic inflammatory disorders

The effect of the gene region on chromosome 2q33 containing the CD28 and th e cytotoxic T-lymphocyte associated (CTLA4) genes has been investigated in several diseases with chronic inflammatory nature. In addition to celiac di sease ICD), type I diabetes, Grave's disease, rheumatoid arthritis and mult iple sclerosis have all demonstrated associations to the A/G single nucleot ide polymorphism (SNP in exon 1, position +49 of the CTLA4 gene. The purpos e of this study was to investigate this gene region in a genetically homoge neous population consisting of 107 Swedish and Norwegian families with CD u sing genetic association and linkage methods. We found a significant associ ation with preferential transmission of the A-allele of the exon 1 +49 poly morphism by using the transmission disequilibrium test (TDT). Suggestive li nkage of this region to CD was moreover demonstrated by non-parametric link age (NPL) analysis giving a NPL-score of 2.1. These data strongly indicates that the CTLA4 region is a susceptibility region in CD. Interestingly, of the several chronic inflammatory diseases that exhibit associations to the CTLA4 +49 A/G dimorphism, CD appears to be the only disease associated to t he A allele. This suggests that the +49 alleles of the CTLA4 gene are in li nkage disequilibrium with two distinct disease predisposing alleles with se parate effects. The peculiar association found in the gut disorder CD may p ossibly relate to the fact that the gastrointestinal immune system, in cont rast to the rest of the immune system, aims to establish tolerance to forei gn proteins.