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-DQA1*05 and HLA-DQB1*02, which encode the DQ2 heterodimer. These alleles are commonly inherited in cis with DRB1*03:01, 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 DRB1*03:01-carrying haplotypes in CD susceptibility. A family (274 trios) and a case-control sample (369 CD cases/461 controls) were analyzed. DRB1*03:01-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 DRB1*03:01-carrying haplotypes, and this effect only involves individuals possessing a single copy of DQB1*02. CD risk for these individuals is similar to the one conferred by inherit DQA1*05 and DQB1*02 in trans. It seems that an additional CD susceptibility factor is present in the AH 8.1 but not in other DRB1*03:01-carrying haplotypes. This factor could be share