title: Plasma S/R ratio of warfarin co-varies with VKORC1 haplotype.
abstract: We recently reported that the low-dose VKORC1*2 haplotype is an important genetic determinant for warfarin dose requirement and is associated with difficulties to attain stable therapeutic prothrombin time--International Normalized Ratio in patients undergoing anticoagulation therapy. The aim of this study was to investigate whether patients with VKORC1*2 compared with patients carrying high-dose haplotypes VKORC1*3 or VKORC1*4 had different warfarin S/R ratios in their plasma, and whether that was related to CYP2C9 variants CYP2C9*2 and CYP2C9*3 or other factors. Samples from patients previously haplotyped for VKORC1 and measured for plasma warfarin concentration were genotyped for the CYP2C9 variants CYP2C9*2 and CYP2C9*3. Nonparametric statistical analysis was performed to elucidate whether there was any significant difference in the warfarin S/R ratio between the two patient groups. Our result shows that there is a significant difference (P<0.01) in warfarin S/R ratios between VKORC1*2 and VKORC1*3 or VKORC1*4 patients. This difference did not originate from CYP2C9 variants CYP2C9*2 and CYP2C9*3. We speculate that VKORC1 haplotypes possibly are linked to some unidentified factors involved in the metabolic clearance of warfarin enantiomers. Dose-dependent variations in (S)-warfarin and (R)-warfarin clearance in these patients can also be a probable explanation for the difference in warfarin S/R ratios.
authors.affiliation: Department of Clinical Chemistry, Laboratory Medicine, University Hospital, Linköping, Sweden. Majid.Osman@lio.se
authors.forename: Abdimajid
authors.initials: A
authors.lastname: Osman
authors.forename: Camilla
authors.initials: C
authors.lastname: Enström
authors.forename: Tomas L
authors.initials: TL
authors.lastname: Lindahl
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010597:Pharmacogenetics; D013237:Stereoisomerism; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*
chemical_list: D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases