B-112 HLA-DQ Genotypes as Predictors of Serological Positivity for Celiac Disease in Pediatric Patients

Abstract Background Celiac disease (CeD) is a chronic autoimmune disorder that can affect people of any age. Both ingestion of gluten and the presence of human leukocyte antigens (HLA)-DQ2 or DQ8 are required for disease development. In adults, correlation between HLA-DQ2/DQ8 allele combinations and tissue transglutaminase (tTG) antibody positivity has been well described. In comparison, this association in pediatric patients is less defined. In this study, we evaluated the roles of HLA-DQ2 and HLA-DQ8 as predictors of tTG-IgA positivity in a pediatric cohort, aiming to enhance understanding of CeD risk assessment in this diagnostic group. Methods Retrospective data were collected from individuals who underwent CeD diagnostic testing at Mayo Clinic Laboratories between 2011 and 2024; all patients were tested for total IgA, HLA-DQ typing, and tTG-IgA. Total IgA was measured using quantitative nephelometry on the BN™ II System (Siemens); HLA-DQ typing was performed using reverse sequence-specific oligonucleotide (SSO) DNA typing (LABType SSO kits, One Lambda, Thermo). tTG-IgA was tested using an enzyme-linked immunosorbent assay (QUANTA Lite® h-tTG IgA, Werfen Diagnostics). Those with total IgA below the age-specific reference interval were excluded from this analysis. Logistic regression was used to evaluate the association between HLA-DQ haplotypes and tTG-IgA positivity to assess the risk gradient across different HLA-DQ genotypes in children. Results The cohort identified in this study consisted of 115,499 individuals for whom total IgA, HLA-DQ typing and tTG-IgA testing was performed. Within this cohort, 20,676 (17.9%) were pediatric patients (age<=18 at the time of testing). Pediatric patients tested for CeD exhibited a slightly higher prevalence of at least one copy of HLA-DQ2 or DQ8 compared to adults (57.6% vs 55.4%, p<0.001). Additionally, these patients showed significantly higher rates of tTG-IgA positive across all genotypes, particularly those carrying HLA-DQ2.5 or DQ8, with positivity rates 1.2 to 2.3 times higher than in adults (p<=0.01). However, in non-permissive genotypes, the positivity rates were 0.3% (p=0.95), for both populations, indicating comparable specificity. Individuals with homozygous HLA-DQ2.5/DQ2.5 and HLA-DQ2.5/DQ2.2 showed the highest risks for tTG-IgA positivity with ORs of 85.7 (95% CI: 55.1-137.7) and 78.5 (95% CI: 51.3-124.3), respectively. Moderate risk was observed for HLA-DQ2.5/DQ8 with an OR of 49.0 (95% CI: 32.1-77.3), followed by single copy HLA-DQ2.5 (OR=35.0, 95% CI: 24.0-53.4) and homozygous HLA-DQ8/DQ8 (OR=21.7, 95% CI: 11.7-39.4). Although single copies of HLA-DQ2.2 and HLA-DQ8 showed lower risks with ORs of 5.4 and 8.9 (95% CI: 3.2-9.2 and 5.7–13.9), their combination increased the OR to 22.6 (95% CI: 13.0-39.2), similar to homozygous HLA-DQ8. Conclusion This large cohort study demonstrates the predictive value of HLA-DQ genotypes for pediatric CeD seropositivity. Notably, pediatric patients showed slightly higher prevalence and positivity rates compared to adults, particularly among those with homozygous HLA-DQ2.5/DQ2.5 and HLA-DQ2.5/DQ2.2 genotypes, which exhibited the highest risks for tTG-IgA positivity. The findings confirm that HLA-DQ2.5 is the main driver of serology positivity and suggest that HLA-DQ8 also influences serological positivity in pediatric patients, which can enhance targeted screening and potentially inform decisions regarding the necessity of duodenal biopsy.