HLA in coeliac disease families: A novel test of risk modification by the ‘other’ haplotype when at least one DQA1*05‐DQB1*02 haplotype is carried

Abstract

Predisposition to coeliac disease (CD) involves HLA genes. We investigated whether any haplotypes modify risk when carried trans to a known high-risk haplotype, DQA1*05-DQB1*02. Earlier attempts to rank levels of risk contributed by the 'other' haplotype were burdened by use of case-control populations; haplotype frequencies were estimated and homozygosity was only presumed. In contrast, exact haplotypes can be determined and allele transmission can be traced in families. A similar study in narcolepsy reported strata of different degrees of predisposition, attributable to the 'other' haplotype. A gene dosage effect similar to that described for DQB1*02 in CD, has also been reported in narcolepsy. We genotyped 439 simplex/multiplex trios for DQA1 and DQB1. We designed a new statistic to test risk modulation by the trans haplotype, even if the affected offspring was homozygous. We tested for significant deviation in transmission of the 'other' haplotype, i.e., modification of DQA1*05-DQB1*02 risk. We also addressed the proposed difference in risk, between DQA1*05-DQB1*02 homozygotes and DQA1*05-DQB1*02/DQA1*0201-DQB1*02 heterozygotes, reported in Southern Europe. We confirmed a DQB1*02 gene dosage effect. However, no haplotypes were found to modify risk when carried trans to DQA1*05-DQB1*02, except DQA1*05-DQB1*02 and DQA1*0201-DQB1*02 which were already known. We did not find credible evidence for a difference in risk conferred by DQA1*05-DQB1*02 and DQA1*0201-DQB1*02, when carried with DQA1*05-DQB1*02. The new test, which directly inspects haplotype transmissions rather than estimated haplotype frequencies, was used to demonstrate that the 'other' haplotype (except DQA1*05-DQB1*02 and DQA1*0201-DQB1*02) does not modify risk conferred by DQA1*05-DQB1*02. The test is applicable to other diseases.

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

“…[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. The homozygous DQA1*05-DQB1*02 genotype produces 100% DQ2 molecules.…”

“…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).…”

Association study of IL2/IL21 and FcgRIIa: significant association with the IL2/IL21 region in Scandinavian coeliac disease families

“…11,12 All affected family members strictly fulfilled the ESPGAN (European Society of Pediatric Gastroenterology and Nutrition) diagnostic criteria. 13 …”

HLA DQ Gene Dosage and Risk and Severity of Celiac Disease

“…17 18 The data using direct DQ genotyping are limited to studies in European and North African countries. [19][20][21][22] There is also some evidence of a dosage effect of these genes: Studies in predominantly pediatric Norwegian and Sardinian populations suggested that those who are homozygous for DQB1*02 in the presence of DQA1*05 have a higher risk of developing CD and do so with greater severity. 23,24,21 A second study from Spain suggested that a double dose of DQB1* 02 was associated with earlier age of onset and shorter delay to diagnosis.…”