The effect of the CYP4F2 V433M polymorphism on maintenance warfarin dosing: a meta-analysis

Context: Although VKORC1 and CYP2C9 gene polymorphisms affect warfarin dosing they only account for one-third of inter-patient variability in therapeutic warfarin dose.   CYP4F2 is a mitochondrial ω-hydroxylase catalyzing the first step in the degradation of vitamin K1.  Some studies have indicated that the CYP4F2 V433M polymorphism (rs2108622, C>T allele) increases warfarin dose, while others have not. 

Purpose: To quantify the overall effect of the CYP4F2 V433M polymorphism on warfarin dose. Data Sources: We conducted a systematic search of published literature using Embase, Medline (through PubMed), and Google Scholar to identify relevant studies.

Methods: We identified 139 studies and 21 met our inclusion criteria.  From eligible studies, we extracted the sample size, minor T allele frequency, warfarin dose effect, percentage increase in warfarin dose per T allele, and adjusted R²value.  The primary outcome was increase in warfarin dose per T allele. 

Results: Effects in 13 studies have been corroborated by 2 independent reviewers and show a 5.6% (95% CI 3.5-7.6%) increase in mean weekly warfarin dose per T allele of the rs2108622 polymorphism, quantifying the significance of CYP4F2 genotype.  Limitation: The clinical significance of a 5.6% increase in warfarin dose was not assessed.

Conclusion: The presence of the CYP4F2 V433M polymorphism results in a statistically significant increase in warfarin dose.  In reducing the activity of the CYP4F2 enzyme per T allele, more Vitamin K is available requiring a relatively higher warfarin dose to achieve therapeutic effect.