HLA genotyping in pediatric celiac disease patients

Abstract

Celiac disease (CD) is a chronic inflammatory disease in the small intestine triggered by gluten uptake that occurs in genetically susceptible individuals. HLA-DQ2 protein encoded by HLA-DQA1*05 and DQB1*02 alleles is found in 90-95% of CD patients. All of the remaining patients carry HLA-DQ8 protein encoded by HLA-DQA1*03 and DQB1*03:02 alleles. Specific HLA-DQ genotypes define different risk for CD incidence. Presence of susceptible HLA-DQ genotypes does not predict certain disease development, but their absence makes CD very unlikely, close to 100%. Here we presented for the first time the distribution of HLA-DQ genotypes in the group of pediatric celiac patients from the University Children's Hospital, Belgrade, Serbia and estimated risk for CD development that these genotypes confer. Seventy three celiac disease patients and 62 healthy individuals underwent genotyping for DQA1, DQB alleles and DRB1 allele. 94.5% of patients carried alleles that encode DQ2 protein variant and 2.7% carried alleles that encode DQ8 protein variant. Two patients carried single DQB1*02 allele. No patients were negative for all the alleles predisposing to CD. The highest HLA-DQ genotype risk for CD development was found in group of patients homozygous for DQ2.5 haplotype, followed by the group of heterozygous carriers of DQ2.5 haplotype in combination with DQB1*02 allele within the other haplotype. The lowest risk was observed in carriers of a single copy of DQB1*02 or DQA1*05 allele or other non-predisposing alleles. HLA genotyping, more informative than serological testing commonly used, proved to be a useful diagnostic tool for excluding CD development.

HLA‐DQ genotypes relative risks for celiac disease in Arabs: A case‐control study

“…Our findings reinforce and confirm the observations made by other investigators that the risk of developing CD is greater for homozygous HLA‐DQ2.5 individuals (carrying a double copy of DQB1*02 ) than it is for heterozygous HLA‐DQ2.5 individuals (carrying a single copy of DQB1*02 ), demonstrating a gene dosage effect (OR 5.04 vs OR 1.67). This suggests that homozygous HLA‐DQ2.5 molecules are more efficient in presenting gliadin peptides to T cells in the small intestine and inducing a stronger immune response than heterozygous HLA‐DQ2.5 . Another important observation from our data is the synergistic gene effect demonstrated by the DQ8 and DQ2.2 heterodimers when one of them is combined with a DQ2.5 heterodimer on the surface of antigen presenting cells in the same individual, which could be due to a broadening repertoire of gluten peptides presented to T cells in the intestine because these heterodimers contain different positively charged pockets on their surfaces that bind to the negatively charged glutamate on gluten peptides .…”

“…4,11,[13][14][15][20][21][22] This suggests that homozygous HLA-DQ2.5 molecules are more efficient in presenting gliadin peptides to T cells in the small intestine and inducing a stronger immune response than heterozygous HLA-DQ2.5. 23 Another important observation from our data is the synergistic gene effect demonstrated by the DQ8 and DQ2.2 heterodimers when one of them is combined with a DQ2.5 heterodimer on the surface of antigen presenting cells in the same individual, which could be due to a broadening repertoire of gluten peptides presented to T cells in the intestine because these heterodimers contain different positively charged pockets on their surfaces that bind to the negatively charged glutamate on gluten peptides. [24][25][26] Interestingly, we noted a higher frequency of heterozygous DQ8 (13.0% vs 2.2%) and…”

“…Among all DQ heterodimers, the DQ2.5 heterodimer induces the strongest T‐lymphocyte response via its greater binding affinity to form stable complexes with gluten peptide fragments. This stability allows DQ2.5 heterodimer to induce a T‐cell reactivity of a larger magnitude than either DQ8 or DQ2.2, thereby increasing the likelihood that the T‐cell response reaches the pathogenic threshold …”

Novel genetic risk variants for pediatric celiac disease

“…Selected variants were subsequently validated in pediatric celiac disease patients of Greek ( n  = 109) [17] and Serbian ( n  = 73) [18] descent and their healthy counterparts ( n  = 111 and n  = 32, respectively). The diagnosis of celiac disease was based on the criteria of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) [19].…”

Early Infant Feeding Practices May Influence the Onset of Symptomatic Celiac Disease

“…About 90-95% of the CD patients carry the HLA-DQ2 protein, the rest carries HLA-DQ8 protein. The prevalence of the HLA-DQ2 and HLA-DQ8 in the general population is 25-40% compared to 1% prevalence of CD showing that the presence of these genotypes is necessary but not sufficient for the onset of the disease [2]. The answer lies in other genetic and environmental risk factors.…”