Utility of human leukocyte antigen DQ2 and DQ8 genotypes in Celiac disease: Two sides of the coin

Abstract

Human Leukocyte Antigen (HLA) DQ2 and DQ8 are the known risk genotypes for Celiac Disease. Diagnosis of celiac disease requires serology testing and intestinal biopsy however, genetic testing could also be implemented because of its high negative predictive value. Our study, initiated prior to the publication of 2020 guidelines, evaluated the utility of HLA DQ2 and DQ8 genotyping in the cohort of 537 children with celiac disease and their 1420 first-degree relatives. We attempted to evaluate its applicability in low-middle-income countries like India. Prevalence of celiac disease was observed at 18.52% and 15.68% based on serological and histopathological diagnosis in first-degree relatives. HLA DQA1*0501 and DQB1*0201 alleles were the most frequently observed alleles in index cases (84.4% versus 86.4%), biopsy proven first-degree relatives (77.9% vs 72.15) and serology negative first-degree relatives (67.7% vs 58.3%) (p<0.001). A strong association of DQA1*0501 and DQA1*0301 alleles was observed with high serology positivity (p<0.05). The majority of the subjects in our cohort had histopathologic scores of 3c (54.80%), 3b (22.13%), 3a (22%) and grade 2 (1.05%) (p<0.001). HLA DQB1*0201 was observed as 100% in cases with Marsh grade 2, 72.5% in grade 3a, 82.7% in grade 3b and 85.6% in grade 3c (p=0.017) mucosal lesions. HLA DQA1*0501 and DQB1*0201 alleles of the DQ2 genotype also predicted the severity of intestinal mucosal damage assessed by Marsh grading when used in conjunction with anti-tTG-IgA. When performed in-house using polymerase chain reaction-sequence specific primers method, the assay was economical in identification of mucosal severity in index cases and the first-degree relatives. Its value as a model for additive predictive value in the diagnostic algorithm of cases with tTG-IgA less than 10 times of the upper limit of normal needs further evaluation.