Influence of CYP2C9 and VKORC1 Polymorphisms on Warfarin Dose and Anti-Coagulative Effect in Chinese Population

OBJECTIVE To investigate the contribution of cytochrome P450 2C9(CYP2C9) and vitamin K epoxide reductase complex 1(VKORC1) genotypes to warfarin dose requirement,and try to establish an individualized warfarin therapeutic regimen in Chinese population.METHODS CYP2C9 and VKORC1 genotypes were deter mined by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) technique in Chinese healthy volunteers and patients(with stable warfarin dose requirements and within the target international normalized ratio 1.5-3.0),and patients' clinical data including age,gender,body weight,height,serum albu min,warfarin dose were recorded.RESULTS CYP2C9 genotyping showed that the frequencies of *1/*1,*1/*2,*1/*3 were 90.5%(200/221),0.5%(1/221) and 9.0%(20/221) for healthy volunteers,respectively,and the frequencies were 91.6%(174/190) for patients,0%(0/190) and 8.4%(16/190) for patients,respectively;VKORC1(-1 639) genotyping showed that in healthy subjects the frequencies of AA,AG,GG were 82.4%(182/221),17.6%(39/221) and 0%(0/221),respectively,which for patients was 85.8%(163/190),13.2%(25/190) and 1.1%(2/190),respectively.Warfarin doses in VKORC1-1639AA patients were significantly lower than those in GA+GG patients[(2.61±0.84) mg·d-1 vs.(4.44±0.87) mg·d-1],and the doses in CYP2C9*1/*3 patients were also lower than that in *1/*1 patients[(2.29±0.83) mg·d-1 vs.(2.98±1.09) mg·d-1].4.2% and 39.4% variation in warfarin dose could be explained by CYP2C9 and VKORC1 genotype among Chinese patients.Age,weight,CYP2C9 and VKORC1 polymorphism together could account for 55.0%(r2=0.55) of the inter-individual variation in warfarin dose requirement.CONCLUSION The use of CYP2C9 and VKORC1 polymorphism and clinical covariates could predict warfarin dose in Chinese population,and the dosing regimen taking into account the contribution of age,weight,CYP2C9 and VKORC1 genotypes has the potential to improve the safety of warfarin anticoagulation therapy.