Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications

Background The cytochrome P450 CYP2C9 is responsible for the metabolism of S-warfarin. Two known allelic variants CYP2C9*2 and CYP2C9*3 differ from th e wild type CYP2C9*1 by a single aminoacid substitution in each case. The a llelic variants are associated with impaired hydroxylation of S-warfarin in in-vitro expression systems. We have studied the effect of CYP2C9 polymorp hism on the in-vivo warfarin dose requirement. Methods Patients with a daily warfarin dose requirement of 1.5 mg or less ( low-dose group, n=36), randomly selected patients with a wide range of dose requirements from an anticoagulant clinic in north-east England (clinic co ntrol group, n=52), and 100 healthy controls from the community in the same region were studied. Genotyping for the CYP2C9*2 and CYP2C9*3 alleles was done by PCR analysis. Case notes were reviewed to assess the difficulties e ncountered during the induction of warfarin therapy and bleeding complicati ons in the low-dose and clinic control groups. Findings The odds ratio for individuals with a low warfarin dose requiremen t having one or more CYP2C9 variant alleles compared with the normal popula tion was 6.21 (95% CI 2.48-15.6). Patients in the low-dose group were more likely to have difficulties at the time of induction of warfarin therapy (5 .97 [2.26-15.82]) and have increased risk of major bleeding complications ( rate ratio 3.68 [1.43-9.50]) when compared with randomly selected clinic co ntrols. Interpretation We have shown that there is a strong association between CYP 2C9 variant alleles and low warfarin dose requirement. CYP2C9 genotyping ma y identify a subgroup of patients who have difficulty at induction of warfa rin therapy and are potentially at a higher risk of bleeding complications.