CYP4F2 genetic variant alters required warfarin dose

Abstract

Warfarin is an effective, commonly prescribed anticoagulant used to treat and prevent thrombotic events. Because of historically high rates of drug-associated adverse events, warfarin remains underprescribed. Further, interindividual variability in therapeutic dose mandates frequent monitoring until target anticoagulation is achieved. Genetic polymorphisms involved in warfarin metabolism and sensitivity have been implicated in variability of dose. Here, we describe a novel variant that influences warfarin requirements. To identify additional genetic variants that contribute to warfarin requirements, screening of DNA variants in additional genes that code for drug-metabolizing enzymes and drug transport proteins was undertaken using the Affymetrix drug-metabolizing enzymes and transporters panel. A DNA variant (rs2108622; V433M) in cytochrome P450 4F2 (CYP4F2) was associated with warfarin dose in 3 independent white cohorts of patients stabilized on warfarin representing diverse geographic regions in the United States and accounted for a difference in warfarin dose of approximately 1 mg/day between CC and TT subjects. Genetic variation of CYP4F2 was associated with a clinically relevant effect on warfarin requirement.

Figures

Figure 1

Depiction of relative statistical relationships of SNPs with predicted warfarin therapeutic dose, Marshfield model. The P value (log scale) for each polymorphism, comparing residuals for warfarin dose, was plotted. Dashed line shows the adjusted threshold for significance.

Figure 2

Warfarin therapeutic dose by CYP4F2 genotype and study site. Box plots of dose by study site and CYP4F2 (all cases). Boxes extend from the 25th to the 75th percentiles, with a horizontal line at the median and vertical lines extending to the 10th and 90th percentiles.

Figure 3

Marshfield model residuals by CYP4F2 genotype and study site (*1 genotypes only). Model adjusts for age, gender, body surface area, indication for warfarin, VKORC1, and CYP2C9. Boxes extend from the 25th to the 75th percentiles, with a horizontal line at the median and vertical lines extending to the 10th and 90th percentiles.