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CYP2C9, VKORC1, and CYP4F2 polymorphisms and pediatric warfarin maintenance dose: a systematic review and

Masanobu Takeuchi1,2, Tohru Kobayashi1,3, Tina Biss4,5

  • 1Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, ON, Canada.

The Pharmacogenomics Journal
|November 2, 2019
PubMed

Insights

Genetic variations in CYP2C9 and VKORC1 influence warfarin dosage in children, requiring lower doses for specific genotypes. CYP4F2 polymorphisms, however, showed no significant effect on pediatric warfarin maintenance dose.

Area of Science:

  • Pharmacogenomics
  • Pediatric Medicine
  • Clinical Pharmacology

Background:

  • Warfarin dosage in children is complex and influenced by genetic factors.
  • Previous studies on the impact of cytochrome P450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P450 4F2 (CYP4F2) polymorphisms on warfarin maintenance dose in pediatric populations have yielded conflicting results.

Purpose of the Study:

  • To conduct a systematic review and meta-analysis to clarify the effect of CYP2C9, VKORC1, and CYP4F2 polymorphisms on warfarin maintenance dose in children.

Main Methods:

  • A comprehensive literature search was performed in MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials up to July 23, 2017.
  • Nine studies involving 745 pediatric participants were included in the meta-analysis.
  • Dose differences were analyzed using standardized mean difference (SMD) or mean difference (MD) with 95% confidence intervals (CI).

Main Results:

  • Patients with variant CYP2C9 genotypes (*1/*2, *1/*3, *2/*2, *2/*3, *3/*3) required significantly lower warfarin maintenance doses compared to those with CYP2C9 *1/*1 (SMD = -0.610).
  • Individuals with VKORC1-1639GA or AA genotypes needed a lower warfarin maintenance dose than those with VKORC1-1639GG (SMD = -0.666).
  • No significant association was found between CYP4F2 polymorphisms and warfarin maintenance dose in children (MD = 0.005 mg/kg/day).

Conclusions:

  • CYP2C9 and VKORC1 genetic variants significantly impact warfarin maintenance doses in children.
  • CYP4F2 polymorphisms do not appear to influence warfarin dosage requirements in the pediatric population.
  • These findings support the role of pharmacogenetics in optimizing warfarin therapy for children.

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