To Study the Association of HLA‐DQ2/8 With Celiac Disease and Identifying Proxy‐SNPs for Predicting Their Presence in North Indian Population

Celiac disease (CD) risk conferred by HLA-DQ2 and DQ8 varies significantly across populations. In north India, where CD is as prevalent as in European populations, reports on the association of HLA-DQ2 and DQ8 with CD are limited. In a north Indian CD case-control cohort (459 CD and 450 controls), known CD-associated risk HLA-DQ alleles, HLA-DQA1*05:01/02:01/03:01 and HLA-DQB1*02/*03:02, were genotyped using SSP-PCR to uncover their frequency and association with CD. Published dense Illumina_Immunochip genotyping data of the study cohort were used to identify proxy-SNPs for HLA-DQ genotypes and their alleles. We also investigated the correlation between common CD phenotypes and DQ2/8 genotypes. Ninety-nine percent of the CD patients were found to carry HLA-DQ2.5, DQ2.2 or 8. HLA-DQA1*05:01 (OR = 5.86 [4.39-7.81], p < 0.0001) and HLA-DQB1*02 (OR = 16.61 [11.37-24.25], p < 0.0001) were identified as the strongest susceptibility alleles. HLA-DQ2.5 was present in 92% of patients and conferred the highest CD risk (OR = 29.01 [19.56-43.00], p < 0.00001), while DQ8 appeared protective (OR = 0.42 [0.25-0.70], p < 0.0001). HLA-DQ2.5/8 and HLA-DQ2.5/2.2 were found significantly associated with serum anti-tTG-IgA and skin conditions, respectively, among CD patients. rs1129740, rs9273012 and rs7744001 were identified as proxy-SNPs to efficiently predict the presence/absence of DQ2.5, DQ2.2, DQ8 and its alleles. This was the first well-powered study to evaluate the susceptibility of HLA-DQ in CD among the north Indian population. HLA-DQ2.5 showed a strong association with CD, conferring a higher disease risk, while DQ8 appeared protective, and the contribution of DQ2.2 was inconclusive. Three proxy-SNPs, rs1129740, rs9273012 and rs7744001, could be utilized to predict HLA-DQ genotypes as a cost-effective alternative for CD risk assessment.