The Influence of CYP4F2 Polymorphisms on Warfarin Doses in Korean Patients with a Variety of Diseases

Abstract

Warfarin, as a common oral anticoagulant, is used to prevent and treat thromboembolic diseases such as atrial fibrillation (AF), heart valve replacement, deep venous thrombosis, and pulmonary embolism. Warfarin has many disadvantages such as narrow therapeutic index and wide dose variation of interindividual response, and its stable dosage is influenced by a variety of factors. Thus, determining warfarin therapy is challenging. Several studies have shown that genetic polymorphisms affect warfarin pharmacodynamics, especially CYP2C9 and vitamin K epoxide reductase complex subunit 1 (VKORC1). One study demonstrated that the VKORC1 genotype can explain about 27% of warfarin dose variation, and the CYP2C9 genotype can explain about 7% of the warfarin dose variation in Asian patients. Combining this with other non-genetic factors, VKORC1 and CYP2C9 in warfarin pharmacokinetics and pharmacodynamics account for approximately 50% of inter-individual warfarin dose variation. However, half of the variation sources are still unknown. CYP4F2 is an enzyme that can catalyze multiple reactions and affect warfarin dose. CYP4F2 is a primary liver vitamin K1 oxidase that catalyzes the metabolism of vitamin K1 to hydroxy-vitamin K1 and removes vitamin K from the vitamin K cycle, which can lead to less vitamin K available for clotting factor activation. The physiologic role of CYP4F2 in the vitamin K/warfarin pathway is controversial. Some studies have shown that the CYP4F2 genotype can affect warfarin dose. Compared to wild-type patients, patients with CYP4F2 variants need higher warfarin dose. But some papers reported that the CYP4F2 genotype did not affect warfarin dose. In addition, the CYP4F2 gene influence on warfarin dosage has not been frequently tested in the Korean population. Therefore, we sought to determine if CYP4F2 could affect warfarin dosage in Korean patients with a variety of diseases.