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

The gene encoding vitamin K epoxide reductase complex subunit I (VKORCI), a component of the enzyme that is the therapeutic target site for warfarin, has recently been identified. In order to investigate the relationship between VKORCI I and warfarin dose response, we studied the VKORCI gene (VKORCI) 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 anti coagulation. Three of these had serum warfarin concentrations within the therapeutic range of 0.7-2.3 mg/l and showed wild-type VKORCI sequence. The fourth warfarin resistant individual had consistently high (greater than or equal to5.7 mg/l) serum warfarin concentrations, yet had no clinically discernible cause for warfarin resistance. VKORCI showed a heterozygous 196G-->A transition that predicted aVal66Met substitution in the VKORCI 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 K-I 2,3 epoxide suggesting that their basal vitamin K epoxide reductase activity was not adversely affected by the VKORCI Val66Met substitution. The association between a nucleotide transition in VKORCI and pharmacodynamic warfarin resistance supports the hypothesis that VKORCI is the site of action of warfarin and indicates that VKORCI sequence is an important determinant of the warfarin dose response.