Title: Pharmacodynamic resistance to warfarin is associated with nucleotide substitutions inVKORC1
Abstract: <h3>Summary</h3> <i>Background:</i>Vitamin K epoxide reductase subunit 1 (VKORC1) is the molecular target of coumarin anticoagulants and mutations in<i>VKORC1</i> have been identified previously in individuals who required high warfarin doses.<i>Objective:</i>Detailed characterization of the relationship between variation in<i>VKORC1</i> and the warfarin resistance phenotype.<i>Patients and methods:</i>Serum warfarin concentration and coagulation parameters were determined in 289 subjects who required warfarin doses >20 mg day<sup>−1</sup>. The<i>VKORC1</i> sequence was studied in selected study subjects.<i>Results:</i>Twenty‐eight out of 289 (10%) subjects had serum warfarin >2.3 mg L<sup>−1</sup> during stable therapeutic anticoagulation indicating pharmacodynamic warfarin resistance. Detailed analysis of 15 subjects from this group showed that eight out of 15 (53%) had nucleotide substitutions in<i>VKORC1</i> predictive of p.V66M, p.L128R, p.V54L or p.D36Y.<i>VKORC1</i> was normal in the remaining seven out of 15 (47%) subjects and in nine out of nine (100%) subjects with high warfarin dose requirement not caused by pharmacodynamic resistance. At referral, subjects with<i>VKORC1</i> mutations received a median warfarin dose of 32 mg day<sup>−1</sup> (range 22–55) and had a median serum warfarin concentration of 4.6 mg L<sup>−1</sup> (range 2.6–9.0).<i>VKORC1</i> substitutions were associated with a requirement for high warfarin doses but not with adverse clinical events. Family members with<i>VKORC1</i> nucleotide substitutions and not receiving warfarin had undetectable PIVKA‐II and K<sub>1</sub> epoxide (K<sub>1</sub>O).<i>Conclusions:</i>Nucleotide variations in<i>VKORC1</i> are a common cause of pharmacodynamic warfarin resistance but are not associated with adverse outcome during anticoagulation. Mutations associated with warfarin resistance do not cause a discernible defect in VKORC1 reductase function.