Modifying effect of HLA haplotypes located trans to DQB1*02-DRB1*03 in celiac patients of Southern Europe

The DQ2 heterodimer, encoded by the human leukocyte antigen (HLA)-DQA 1 *05-DQB 1*02 alleles, is the major genetic susceptibility factor for celiac disease (CD), However, the risk associated to HLA alleles varies among populations. While DRBI*03 is almost the only CID susceptibility allele in Northern Europe with a homozygote frequency of around 30%, CD in south European countries is also associated with the DRB1*07, and DRB1*03 homozygotes patients are rare. Some authors have suggested that DQB1*02-DRBI*03/DQB1*02-DRBI*03 and DQB1 *02-DRB1 *03/DQB1 *02-DRB1 *07 may confer different risk susceptibility to CD. This hypothesis, however, has not been demonstrated in a recent family-based study carried out in Finland, suggesting that the proposed differences in risk may be secondary to stratification burdens of case-control studies. To assess this issue, we have investigated the effect of different haplotypes carried trans to DQB1*02-DRBI*03 as additional factors for CD in Spain, using two statistical approaches, a case-control study and a family-based study. We found that DQB1*02-DRBl*03/DQBl*02-DRBI*03 and DQB1*02-DRBI*03/DQB1*02-DRBI*07 were the only combinations that showed a strong and independent association to CD. We did not observe any difference in susceptibility risk conferred by DQB1*02-DRBI*03 and DQB1*02-DRB1*07 when carried trans to DQB1*02DRB1*03, suggesting that variation in HLA haplotype frequencies among populations may not represent real differences in risk to CD development. We also confirmed a gene dosage effect of the DQB1*02-DRBI*03 haplotype estimating that DQB1*02 homozygotes are at fivefold increased risk for CD compared with DQB1*02 heterozygotes. This risk is conferred by the second copy of the DQB1*02 allele and it seems to be independent of the DQA1.