Human Leukocyte Antigen DQ (HLA‐DQ) genotypes and haplotypes and their association with phenotype in patients with celiac disease in India

Background and Aim Human Leukocyte Antigen DQ (HLA‐DQ) genotypes play a permissive role in the genesis of celiac disease (CeD). In this case–control study, we used next‐generation sequencing to determine HLA‐DQA1 and ~DQB1 genotypes and haplotypes associated with CeD in Indian patients. Methods HLA‐DQA1 and ~DQB1 loci were amplified, using long‐range polymerase chain reaction (PCR), from DNA of 259 patients with symptomatic CeD (160 typical and 99 atypical), 45 asymptomatic CeD, 96 potential CeD, and 300 healthy adults. Amplicons were fragmented and sequenced on the Illumina platform, and alleles and haplotypes were assigned by matching against the HLA‐international ImMunoGeneTics (IMGT) database. Results HLA‐DQA1*05:01 (odds ratio [OR] 8.39, 95% confidence interval [CI] 5.64–12.47) and HLA‐DQB1*02:01 (OR 8.59, 95% CI 5.75–12.83) were the genotypes that showed a risk association with symptomatic CeD. Among the haplotypes, HLA‐DQA1*05:01 ~ HLA‐DQB1*02:01 (OR 8.56, 95% CI 5.67–13.19) showed a strong risk association with symptomatic CeD. When comparing symptomatic CeD with subclinical forms (asymptomatic and potential) CeD, HLA‐DQA1*05:01 ~ HLA‐DQB1*02:01 (OR 2.34, 95% CI 1.61–3.43) was significantly associated with risk of symptomatic disease. The strength of association between the HLA‐DQA1*05:01 ~ HLA‐DQB1*02:01 haplotype and the CeD phenotype showed a gradient in the order typical > atypical > asymptomatic > potential CeD. Genotypes consistent with expression of HLA DQ2 and/or 8 were noted in 128 (80%) typical, 73 atypical (74%), 27 (60%) asymptomatic, and 52 (54%) potential CeD participants. Conclusion HLA‐DQA1*05:01 ~ HLA‐DQB1*02:01 (haplotype DQ2.5) showed a very strong risk association with symptomatic CeD in Indian patients. The strength of association showed a gradient of increase from potential to typical CeD, coinciding with a phenotypic change in the celiac iceberg. In the Indian population, HLA‐DQA1*05:01~HLA‐DQB1*02:01 (odds ratio 8.56, 95% confidence interval 5.67–13.19) showed a strong risk association with celiac disease, while other known predisposing genotypes failed to show significant associations. The strength of association of this haplotype weakened progressively with the change of phenotype from typical to atypical to asymptomatic to potential celiac disease. Twenty percent of typical celiac disease patients lacked genotypes capable of expressing DQ2 or DQ8 antigens.