HLA and celiac disease susceptibility: new genetic factors bring open questions about the HLA influence and gene-dosage effects.

Celiac disease (CD) is a chronic inflammatory disorder triggered after gluten ingestion in genetically susceptible individuals. The major genetic determinants are HLA-DQA105 and HLA-DQB102, which encode the DQ2 heterodimer. These alleles are commonly inherited in cis with DRB103∶01, which is associated with numerous immune-related disorders, in some cases contributing with a different amount of risk depending on the haplotype context. We aimed at investigating those possible differences involving DRB103∶01-carrying haplotypes in CD susceptibility. A family (274 trios) and a case-control sample (369 CD cases/461 controls) were analyzed. DRB103∶01-carrying individuals were classified according to the haplotype present (ancestral haplotype (AH) 8.1, AH 18.2 or non-conserved haplotype) after genotyping of HLA-DRB1, -DQA1, -DQB1, -B8, TNF -308, TNF -376 and the TNFa and TNFb microsatellites. We observe that the AH 8.1 confers higher risk than the remaining DRB103∶01-carrying haplotypes, and this effect only involves individuals possessing a single copy of DQB102. CD risk for these individuals is similar to the one conferred by inherit DQA105 and DQB102 in trans. It seems that an additional CD susceptibility factor is present in the AH 8.1 but not in other DRB103∶01-carrying haplotypes. This factor could be shared with individuals possessing DQ2.5 trans, according to the similar risk observed in those two groups of individuals.