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 language | English |
|---|---|
| Pages (from-to) | 581-587 |
| Number of pages | 7 |
| Journal | Journal of Pediatric Gastroenterology and Nutrition |
| Volume | 69 |
| Issue number | 5 |
| DOIs | |
| State | Published - Nov 2019 |
Bibliographical note
Publisher Copyright:© 2019 The Author(s).
Funding
Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal\u2019s Web site (www.jpgn.org). This work was funded by a grant from the Nemours Foundation; Anonymous Foundation Grant. The authors report no conflicts of interest. Copyright \u00A9 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. DOI: 10.1097/MPG.0000000000002480
| Funders | Funder number |
|---|---|
| Nemours Foundation | |
| Anonymous Foundation |
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