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

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 CYP2C1917 (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 CYP2C1917 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 CYP2C1917 to predict PPI-nonresponsive EoE (rs324011 OR [95% CI] = 5.56 [1.33, 20.72], P = 0.022; CYP2C1917 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.

FIGURE 1

Association of CYP2C19^∗17 GOF with outcome of PPI therapy is dose dependent. A, Binary logistic regression modeling of CYP2C19^∗17 as predictor of PPI therapy outcome: (A) non-pH, (B) pH, (C) full, (D) IQR cohorts, and (E) non-IQR cohorts. All models include race, sex, age, PPI dose, and PPI type as covariates. B, Plot of the empirical cumulative distribution () of PPI dose for the pH probe (red) and the non-pH probe (green) cohorts. Solid vertical lines indicate the IQR for the full cohort, dashed vertical lines indicate the medians for the pH probe (red), and the non-pH probe (green) cohorts. The 2 distributions are statistically different from each other (Kolmogorov-Smirnov test P value = 0.015). CI = confidence interval; GOF = gain of function; IQR = interquartile range; PPI-REE = proton pump inhibitor-responsive esophageal eosinophilia.

FIGURE 2

PPI-REE outcome in carriers of STAT6 and CYP2C19^∗17 GOF alleles. Binary logistic regression modeling of: (A) STAT6 rs1059513 as predictor of PPI-REE/complete PPI-REE outcome following 8 weeks of PPI therapy in the full cohort and (B) STAT6 and CYP2C19^∗17 GOF as co-predictors of PPI-REE in the full cohort. All models include race, sex, age, PPI dose, and PPI type as covariates. CI = confidence interval; GOF = gain of function; PPI-REE = proton pump inhibitor-responsive esophageal eosinophilia.