VKORC1 Pharmacogenomics Summary

Abstract

The VKORC1 gene encodes the VKORC1 (vitamin K epoxide reductase) protein, which is a key enzyme in the vitamin K cycle [1,2]. VKORC1 is a 163 amino acid integral membrane protein associated with the endoplasmic reticulum and VKORC1 mRNA is broadly expressed in many different tissues [3]. VKORC1 is responsible for the conversion of vitamin K epoxide to vitamin K, which is the rate-limiting step in the physiological process of vitamin K recycling [4]. The availability of reduced vitamin K is of particular importance for several coagulation factor proteins that require it as a cofactor, including factor VII, factor IX, and factor X [5]. VKORC1 is of therapeutic interest both for its role in contributing to high interpatient variability in coumarin anticoagulant dose requirements and as a potential player in vitamin K deficiency disorders [1]. Warfarin is a commonly prescribed oral anticoagulant used to prevent thromboembolic diseases in patients with deep vein thrombosis, atrial fibrillation, recurrent stroke or heart valve prosthesis [6]. Warfarin, as do other coumarin-type drugs with similar mechanisms of action, acts as an inhibitor of VKORC1; this leads to a reduced amount of vitamin K available to serve as a cofactor for clotting proteins [1]. Although effective warfarin dosing is challenging because of its narrow therapeutic index and high degree of interindividual variability in optimal dosing (between 0.6 and 15.5 mg/day) [7–10]. Inappropriate dosing of warfarin has been associated with a substantial risk of both major and minor hemorrhage [6,10,11]. As the pharmacological target of warfarin, VKORC1 is considered a candidate gene for the variability in warfarin response. Many studies that have attempted to explain the factors that influence warfarin response [6,12,13]. Before the cloning and characterization of VKORC1, it was known that the CYP2C9 genotype of patients played a role in warfarin metabolism and response. The CYP2C9 genotype of the patient explained approximately 10% of the observed variability in the therapeutic warfarin dose [14]. In 2004, VKORC1 was cloned by two different groups, and some variants that conferred warfarin resistance were described [1,2]. The subsequent examination of other VKORC1 variants has shown that polymorphisms in the VKORC1 gene were associated with both high and low-warfarin dose phenotypes in humans. Overall, VKORC1 polymorphisms account for approximately 25% of the variance in stabilized warfarin dose and many studies have consistently showed that VKORC1 genotype seems to be the single biggest predictor of warfarin dose [13,15–17]. Other, nongenetic factors including age, body mass index, sex, weight, and international normalized ratio are also known to play a role in warfarin response and collectively contribute to approximately 20% of variance in dose [18]. Some studies have attempted to define a warfarin dosing algorithm that takes into account both genetic and non-genetic factors predict an optimal warfarin dose [18,19]. In 2007, pharmacogenomic information for warfarin was approved by Food and Drug Administration to be included in the product label stating that VKORC1 and CYP2C9 genotypes may be useful in determining the optimal initial dose of warfarin [20]. A number of large-scale randomized clinical trials are now in progress to develop a globally applicable dosing strategy for warfarin.