Plasma S/R ratio of warfarin co-varies with VKORC1 haplotype.

We recently reported that the low-dose VKORC12 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 VKORC12 compared with patients carrying high-dose haplotypes VKORC13 or VKORC14 had different warfarin S/R ratios in their plasma, and whether that was related to CYP2C9 variants CYP2C92 and CYP2C93 or other factors. Samples from patients previously haplotyped for VKORC1 and measured for plasma warfarin concentration were genotyped for the CYP2C9 variants CYP2C92 and CYP2C93. 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 VKORC12 and VKORC13 or VKORC14 patients. This difference did not originate from CYP2C9 variants CYP2C92 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.