Pharmacodynamic resistance to warfarin associated with a Val66Met substitution in vitamin K epoxide reductase complex subunit I

Abstract

The gene encoding vitamin K epoxide reductase complex subunit I (VKORC 1), a component of the enzyme that is the therapeutic target site for warfarin, has recently been identified. In order to investigate the relationship between VKORC 1 and warfarin dose response, we studied the VKORC I gene (VKORC 1) in patients with warfarin resistance. From a study group of 820 patients, we identified 4 individuals who required more than 25 mg of warfarin daily for therapeutic anticoagulation. Three of these had serum warfarin concentrations within the therapeutic range of 0.7-2. mg/l and showed wild-type VKORC 1 sequence. The fourth warfarin resistant individual had consistently high (≥5.7 mg/l) serum warfarin concentrations, yet had no clinically discernible cause for warfarin resistance. VKORC 1 showed a heterozygous 196G→A transition that predicted aVal66Met substitution in the VKORC 1 polypeptide. This transition was also identified in 2 asymptomatic family members who had never received warfarin. These individuals had normal vitamin-K dependent coagulation factor activities and undetectable serum PIVKA-II and vitamin K1 2, epoxide suggesting that their basal vitamin K epoxide reductase activity was not adversely affected by the VKORC 1 Val66Met substitution. The association between a nucleotide transition in VKORC 1 and pharmacodynamic warfarin resistance supports the hypothesis that VKORC 1 is the site of action of warfarin and indicates that VKORC 1 sequence is an important determinant of the warfarin dose response. © 2005 Schattauer GmbH, Stuttgart.