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Association between CYP2C19 extensive metabolizer phenotype and childhood anti-reflux surgery following failed proton pump inhibitor medication treatment

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Abstract

When pediatric gastroesophageal reflux disease (GERD) that is refractory to proton pump inhibitor (PPI) medication treatment is identified in clinical practice and anti-reflux surgery (ARS) is being considered, genetic factors related to PPI metabolism by the CYP2C19 enzyme are currently not part of the clinical decision-making process. Our objective was to test the hypothesis that the distribution of the extensive metabolizer (EM) phenotypes among children undergoing ARS after failing PPI therapy would differ compared to controls (children with no history of ARS). We conducted a case-control study between children across the Nemours Health System from 2000 to 2014 who received ARS after failing PPI therapy and a control group comprised of healthy children. Our results demonstrated 2.9% of ARSs vs 20.8% of controls were poor metabolizers (PMs), 55.9% of ARSs vs 49.0% of controls were normal metabolizers (NMs), and 41.2% of ARSs vs 30.2% of controls were EMs; p = 0.035. Next, we performed a multiple-regression model to account for race as a potential confounding variable and the EM group was significantly associated with ARS compared to controls (OR 9.78, CI 1.25–76.55, p < 0.03).

Conclusion: Among children with medically refractory GERD despite PPI therapy, carriage of CYP2C19*17 allele corresponding to the EM phenotype was associated with ARS. Prospective comparative personalized medicine effectiveness studies are needed to determine if CYP2C19 genotype-guided dosing improves response to PPI therapy without a corresponding increase in adverse effects in children.

What is known:

• Anti-reflux surgery (ARS) is one of the most common surgical procedures performed in children for the indication of refractory gastroesophageal reflux disease (GERD).

What is new:

• Individualizing PPI medication dosing based on CYP2C19 diplotype may avoid GERD treatment failures and reduce the need for anti-reflux surgery (ARS).

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Abbreviations

ARS:

Anti-reflux surgery

EM:

Extensive metabolizer

GERD:

Gastroesophageal reflux disease

NERD:

Non-erosive reflux disease

NM:

Normal metabolizer

PM:

Poor metabolizer

PPI:

Proton pump inhibitor

SNP:

Single-nucleotide polymorphism

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Funding

Nemours Research Foundation.

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Hepatology and Nutrition, Nemours Children’s Hospital, 13535 Nemours Parkway, Orlando, FL, 32827, USA

    James P. Franciosi & Roberto A. Gomez Suarez

  2. Center for Pharmacogenomics and Translational Research, Nemours Children’s Health System, Jacksonville, FL, USA

    Edward B. Mougey & John J. Lima

  3. Center for Health Care Delivery Science, Nemours Children’s Health System, Jacksonville, FL, USA

    Andre Williams

  4. St. Jude Children’s Research Hospital, Tampa, FL, USA

    Cameron Thomas

  5. Intermountain Medical Center, Murray, UT, USA

    Christa L. Creech

  6. Nova Southeastern University, Fort Lauderdale, FL, USA

    Katherine George

  7. Department of Pathology, A.I. DuPont Hospital for Children, Wilmington, DE, USA

    Diana Corao

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  1. James P. Franciosi
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  2. Edward B. Mougey
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  3. Andre Williams
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  4. Roberto A. Gomez Suarez
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  5. Cameron Thomas
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  9. John J. Lima
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Contributions

James P. Franciosi—study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, statistical analysis.

Edward B. Mougey—study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, statistical analysis.

Andre Williams—analysis and interpretation of data, critical revision of the manuscript for important intellectual content, statistical analysis.

Roberto A. Gomez-Suarez—study concept and design, analysis and interpretation of data, critical revision of the manuscript for important intellectual content.

Cameron Thomas—acquisition of data, analysis and interpretation of data, critical revision of the manuscript for important intellectual content.

Christa L. Creech—acquisition of data, analysis and interpretation of data, critical revision of the manuscript for important intellectual content.

Katherine George—study concept and design, acquisition of data, analysis and interpretation of data, critical revision of the manuscript for important intellectual content.

Diana Corao—acquisition of data, critical revision of the manuscript for important intellectual content.

John J. Lima—study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, statistical analysis.

Corresponding author

Correspondence to James P. Franciosi.

Ethics declarations

All procedures performed involving human participants were in accordance with the ethical standards of the institutional review board and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Conflict of interest

The authors declare that they have no conflicts of interest.

Informed consent

Written informed consent was obtained from parents and age-appropriate children.

Research involving human participants

This study was approved by the Nemours Children’s Health System Institutional Review Board.

Additional information

Communicated by Peter de Winter

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Franciosi, J.P., Mougey, E.B., Williams, A. et al. Association between CYP2C19 extensive metabolizer phenotype and childhood anti-reflux surgery following failed proton pump inhibitor medication treatment. Eur J Pediatr 177, 69–77 (2018). https://doi.org/10.1007/s00431-017-3051-4

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