Pharmacogenomic predictors of proton pump inhibitor response in pediatric eosinophilic esophagitis

Background: Genetic variability has been implicated in the heterogeneous response to proton pump inhibitors (PPIs) in eosinophilic esophagitis (EoE), with variants in CYP2C19 and STAT6 previously associated with treatment outcome. However, the broader pharmacogenomic determinants underlying interindividual variability in PPI response remain incompletely understood.Methods: This study aimed to investigate whether genetic variability in Absorption, Distribution, Metabolism, and Excretion (ADME) genes contributes to PPI response in pediatric EoE. Fifty-eight patients (17 responders, PPI-RE, and 41 non-responders, PPI-NORE) were genotyped using the Drug Metabolizing Enzymes and Transporters (DMET) Plus microarray, covering 231 ADME-related genes. Genetic and clinical data were integrated using a machine learning–based approach to explore determinants of treatment response.Results: CHST3 rs4148944 G/G genotype showed the strongest nominal association with PPI response (p < 0.0064). Integrative analysis revealed combinatorial patterns involving CHST3, CHST11 gene (rs7847), SULT1A2/A3 (rs11859842), and NR1I3 (rs55802895), particularly in the presence of food allergy, which improved patient stratification. Although these additional variants were not individually significant, their combined occurrence—especially in association with food allergy—suggests a potential contribution of both metabolic and regulatory pathways to PPI response variability.Conclusion: Overall, this study provides exploratory, proof-of-concept evidence that the CHST3 rs4148944 G/G genotype, together with other genetic variants and clinical features, may influence PPI response in EoE and contribute to patient stratification. These findings support the potential of integrative pharmacogenomic approaches, although validation in larger cohorts is required.