On the HLA‐DQ(α1*0501, β1*0201)‐associated susceptibility in celiac disease: A possible gene dosage effect of DQB1*0201

Abstract

The HLA-associated susceptibility to develop celiac disease (CD) seems mainly to be conferred by a particular HLA-DQ heterodimer encoded by the DQA1*0501 and DQB1*0201 genes either in cis or in trans position. To study the possible influence of DRB1 or other DQA1 and DQB1 alleles on the CD susceptibility conferred by these DQ genes, we performed genomic HLA typing of 94 CD patients, selected those who carried at least one copy of the DRB1*0301-DQA1*0501-DQB1*0201 haplotype (N = 89) and compared them to 47 random, healthy Norwegians matched with the patients to carry at least one copy of the above haplotype. We found an excess of DQB1*0201 homozygosity in the patients. This was due to an increased frequency of the DRB1*0301-DQA1*0501-DQB1*0201 and DRB1*0701-DQA1*0201-DQB1*0201 haplotypes present on the other chromosome. We propose that, in individuals carrying the DQA1*0501 and DQB1*0201 alleles, the presence of a second copy of the DQB1*0201 allele increases susceptibility to CD.

Risk of Pediatric Celiac Disease According to HLA Haplotype and Country

“…These findings confirm the effects of HLA on the risk of celiac disease that have been observed in earlier prospective studies [10][11][12] and show that the DR3-DQ2 haplotype has a gene-dose effect on the risk of celiac disease autoimmunity. [13][14][15] Our findings also confirm the observation that DR3-DQ2 homozygosity is associated with an earlier age at the onset of celiac disease autoimmunity. 16 In our study, 26% of the children with this highest-risk haplotype had celiac disease autoimmunity by the age of 5 years.…”

Defining the contribution of the HLA region to cis DQ2-positive coeliac disease patients

“…Similar risks were observed in other populations, although these studies were conducted in an ordinary case-control setting, in which haplotypes had to be estimated. [12][13][14] Recently, a family-based study using phase-known haplotypes also demonstrated increased risk for these two genotypes. 11 A possible explanation for the increased risk may reside in the number of DQ molecules capable of gluten presentation that arise from each genotype.…”

“…In particular, the homozygous DQA1*05-DQB1*02/DQA1*05-DQB1*02 (DR3/3) and the heterozygous DQA1*05-DQB1*02/DQA1*0201-DQB1*02 (DR3/7) genotypes were shown to be associated with increased risk. [11][12][13][14] The extended HLA-DR3-DQ2 haplotype includes many other genes that play a role in the immune response and it cannot be excluded that another HLA gene also confers increased risk to coeliac disease. The HLA region is known to display extensive linkage disequilibrium (LD).…”

Resistance to Celiac Disease in Humanized HLA-DR3-DQ2-Transgenic Mice Expressing Specific Anti-Gliadin CD4+ T Cells

“…A second DQ2 molecule (DQ2.2), comprised of DQ␣1*0201/DQ␤1*02, is rarely associated with CD without DQ2.5 (4). Although possession of the DQA1*05 and DQB1*02 alleles confers the primary increased risk of CD, studies have shown that this risk is increased four to six times by homozygosity for the cis-haplotype or a second DQB1*02 allele on the other haplotype (30,31). To verify the functional effect of DQ2 gene dosage on T cell recognition (and further confirm the MHC restriction element for the hybridomas), one T hybridoma line (DB4) was cultured with 〈-gliadin 57-73 Q65E and an irradiated panel of B-lymphoblastoid cell lines (B-LCLs) expressing different DQ␣ and DQ␤ chains (Fig.…”