Pharmacogenomics fail to explain proton pump inhibitor refractory esophagitis in pediatric esophageal atresia

AbstractBackground

Esophagitis is prevalent in patients with esophageal dysmotility despite acid suppression, likely related to poor esophageal clearance. Esophageal atresia (EA) is a classic model of dysmotility where this observation holds true. In adult non-dysmotility populations, failure of esophagitis to respond to proton pump inhibitors (PPI) has been linked to variants in CYP2C19 that influence the activity of the encoded enzyme. It is unknown if CYP2C19 metabolizer phenotype contributes to PPI-refractory, non-allergic esophagitis in EA.

Methods

We performed a cross-sectional study of 314 children with (N = 188) and without (N = 126) EA who were on PPI therapy at the time of endoscopy to evaluate for possible gastroesophageal reflux disease. Patients with eosinophilic esophagitis and/or fundoplication were excluded. Clinical and histology data were collected. Genomic DNA from biopsy samples was genotyped for polymorphisms in CYP2C19.

Results

CYP2C19 metabolizer phenotypes were not associated with presence or severity of esophagitis (P = 0.994). In a multivariate logistic regression adjusted for potential confounders, EA was the strongest and only significant predictor of esophagitis (odds ratio 2.72, P = 0.023). Using negative binomial regression, we found that CYP2C19 phenotype was not a significant predictor of eosinophil count in children with PPI-refractory esophagitis.

Conclusions

Patients with EA are significantly more likely to experience PPI-refractory, non-allergic esophagitis than controls regardless of CYP2C19 metabolizer phenotype, suggesting that factors other than CYP2C19 genetics, including dysmotility, are the primary drivers of esophagitis in EA. CYP2C19 genotype failed to predict PPI-refractory, non-allergic esophagitis in both EA and non-EA children.