CYP2C19 and STAT6 Variants Influence the Outcome of Proton Pump Inhibitor Therapy in Pediatric Eosinophilic Esophagitis

Edward B. Mougey, Andre Williams, Ashlan J. Kunz Coyne, Carolina Gutiérrez-Junquera, Sonia Fernández-Fernández, Maria Luz Cilleruelo, Ana Rayo, Luis Echeverría, Enriqueta Román, Carmen González Lois, Montserrat Chao, Hadeel Al-Atrash, John J. Lima, James P. Franciosi

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Objective: Proton pump inhibitors (PPIs) are an effective treatment for eosinophilic esophagitis (EoE); however, only 30% to 60% of patients respond. Common genetic variants in CYP2C19 and STAT6 associate with PPI plasma concentration and magnitude of inflammatory response, respectively. Our objective was to determine if genetic variation in the genes for CYP2C19 and STAT6 influence differentiation between PPI responsive esophageal eosinophilia versus PPI nonresponsive EoE (PPI-REE, PPI-nonresponsive EoE). Methods: Genomic DNA was isolated from 92 esophageal tissue biopsies collected from participants of a prospective clinical trial of high-dose PPI therapy for esophageal eosinophilia in children. Results: Of the 92 patients examined, 57 (62%) were PPI-REE and 35 (38%) were PPI-nonresponsive EoE. Forty-six of the 92 patients were further characterized by pH probe monitoring; there was no association between reflux index and carriage of CYP2C19∗17 (P = 0.35). In children who received a PPI dose between ≥1.54 and ≤2.05 mg/kg/day, binary logistic regression modeling showed that carriage of CYP2C19∗17 associated with PPI-nonresponsive EoE (odds ratio (OR) [95% confidence interval (CI)] = 7.71 [1.21, 49.11], P = 0.031). Carriage of STAT6 allelic variant rs1059513 predicts PPI-REE (OR [95% CI] = 6.16 [1.44, 26.4], P = 0.028), whereas carriage of STAT6 rs324011 synergizes with CYP2C19∗17 to predict PPI-nonresponsive EoE (rs324011 OR [95% CI] = 5.56 [1.33, 20.72], P = 0.022; CYP2C19∗17 OR [95% CI] = 8.19[1.42, 50.57], P = 0.023). Conclusions:Common variants in CYP2C19 and STAT6 associate with a PPI-nonresponsive EoE outcome of PPI therapy for esophageal eosinophilia suggesting that response rates may be improved by adopting a genotype-guided approach to PPI dosing.

Original languageEnglish
Pages (from-to)581-587
Number of pages7
JournalJournal of Pediatric Gastroenterology and Nutrition
Volume69
Issue number5
DOIs
StatePublished - Nov 2019

Bibliographical note

Publisher Copyright:
© 2019 The Author(s).

Keywords

  • esophagus
  • genotype guided
  • inflammation
  • pharmacogenetics
  • proton pump inhibitor-nonresponsive eosinophilic esophagitis
  • proton pump inhibitor-responsive esophageal eosinophilia

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Gastroenterology

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