Objective:Warfarin is an FDA-approved oral anticoagulant for long-term prevention of thromboembolism. Substantial inter-individual variation in dosing requirements and the narrow therapeutic index of this widely-prescribed drug make safe initiation and dose stabilization challenging. Single nucleotide polymorphisms (SNPs) occurring in CYP2C9, VKORC1, and CYP4F2 genes are known to impact dose, and VKORC1 and CYP4F2 polymorphisms are associated with higher therapeutic dose requirements in our cohort. However, the most advanced regression models using personal, clinical, and genetic factors to predict individual stable dose account for only 50% to 60% of the observed variability in stable theapeutic dose in Caucasians.
Design and Methods:In this study, we used DNA sequence analysis to determine whether additional variants in CYP4F2 and VKORC1 gene coding regions contribute to variable dosing requirements among individuals for whom the actual dose was the highest relative to regression modelpredicted dose.
Results and Conclusions:No novel DNA variants in the coding regions of these genes were identified among subjects requiring high warfarin doses, suggesting that other factors yet to be defined contribute to variability in warfarin dose requirements in this subset of our cohort. Al though warfarin is the most commonly used drug for chronic prevention of thromboembolic events and stroke, it also ranks high among drugs that cause serious adverse events. 1,2 The narrow therapeutic index coupled with substantial inter-individual variability in warfarin dose requirement puts patients at increased risk for hemorrhagic events, and the variability in dose requirements has been attributed to inter-individual differences in medical, personal, and genetic factors. Some factors known to contribute to this variability include valve replacement, diabetes, body surface area (BSA), age, and DNA variants in three enzymes whose activity impacts vitamin K-dependent synthesis of coagulation factors: CYP2C9, VKORC1, and CYP4F2.3-7 Regression models that incorporate these factors have been developed to predict stable dose in order to improve clinical management (eg, time in thereapeutic range) and reduce thrombotic and hemorrhagic events. However, because these algorithms collectively explain only 50% to 60% of dose variability in Caucasians, 8,9 efforts are continuing to identify additional genetic and clinical factors that systematically impact warfarin dose requirements.