A gene telomeric of the HLA class I region is involved in predisposition to both type 1 diabetes and coeliac disease

We have recently shown that an as yet unidentified gene within or in the vi cinity of the HLA complex, in linkage disequilibrium with microsatellite D6 S2223, modifies the risk to develop type 1 diabetes independently of HLA-DR and -DQ genes. This microsatellite is located 2.5 Mb telomeric to HLA-F an d particular alleles at this microsatellite modifies the risk encoded by th e high-risk DRB1*03-DQA1*0501-DQB1*0201 (hereafter called DR3) haplotype. C oeliac disease and type 1 diabetes share some susceptibility HLA class II h aplotypes, in Scandinavia particularly the DR3 haplotype. We therefore inve stigated whether the marker D6S2223 might also be associated with coeliac d isease. In order to keep the contributions from the DRB1-DQA1-DQB1 genes co nstant (i.e., eliminate the effects of linkage disequilibrium to disease as sociated DR and/or DQ alleles), we only used cases and controls being homoz ygous for DR3. We found the frequency of allele 3 at D6S2223 to be reduced among patients with coeliac disease compared to controls, to a similar exte nt as seen in type 1 diabetes, which could not be explained by a different distribution of HLA-B alleles (as ascertained by typing for the MIB microsa tellite). This negatively associated allele 3 at D6S2223 occurred in a homo zygous combination at a significantly lower frequency among patients than c ontrols. Thus, allele 3 at D6S2223 on DR3 haplotypes is associated with red uced susceptibility for development of both type 1 diabetes and coeliac dis ease. This suggests that a gene(s) in the vicinity of D6S2223 is involved i n the pathogenesis of both of these immune-mediated diseases.