Influence Of VKORC1-1639G/A And CYP2C9 1061A/C Polymorphisms On Warfarin Dose

Objective: To investigate the influence of VKORC1-1639G/A and CYP2C9 1061 A/C polymorphisms on warfarin dose in Chinese patients of Han nationality.Methods: PCR-RFLP technology was used to genotype the VKORC1- 1639G/A and CYP2C9 1061A/C polymorphisms in 311 warfarin-treated patients and 198 normal subjects. The mean warfarin dose of patients was compared according to different VKORC1 and CYP2C9 genotypes.Results: 1.There were no significant difference in gender and age composition between the patients and the healthy controls(P>0.05);the frequencies of different genotypes of CYP2C9 1061 and VKORC1-1639 were in agreement with Hardy-Weinberg equilibrium in our study(P>0.05).2. The frequencies of the VKORC1-1639 AA,AG,GG genotypes in the healthy group were 66.2% (131/198),31.3%(62/198) and 2.5%(5/198),respectively, allele frequencies were 81.8% for VKORC1-1639 A and 18.2%for G;frequencies of the CYP2C9 1061 AA,AC,CC genotypes were 84.9% (168/198),14.1%(28/198)and 1%(2/198),respectively, allele frequencies were 91.9% for CYP2C9 1061 A and 8.1% for C;the frequencies of the VKORC1-1639 AA,AG,GG genotypes in the 311 patients were 64.6%(201/311),29.6%(92/311)and 5.8%(18/311),respecti- vely, allele frequencies were 79.4% for VKORC1-1639 A and 20.6%for G;frequencies of the CYP2C9 1061 AA,AC,CC genotypes were 76.8% (239/311),20.3%(63/311)and 2.9%(9/311),respectively, allele frequencies were 87% for CYP2C9 1061 A and 13% for C;There were no significant difference in genotype distribution of VKORC1-1639 and CYP2C9 1061 between the patients and the healthy controls(P>0.05).3. The 311 patients were grouped according to CYP2C9 1061 and VKORC1-1639 genotypes. The patients carrying VKORC1-1639 GG genotype had the highest mean warfarin dose(1.9979±0.3143mg/INR),higher than those carrying AG genotype(1.7841±0.2146mg/INR)(P=0.006),while the patients carrying AG genotype had a higher mean warfarin dose than those carrying AA genotype(1.6397±0.3227mg/INR)(P<0.001),the mean warfarin dose differed significantly among the VKORC1 genotypes(P<0.001);the carriers of CYP2C9 1061 AA genotype had the highest mean warfarin dose (1.7473±0.42897mg/INR) in the CYP2C9 1061 genotype groups,higher than those carrying AC genotype(1.5902±0.3623mg/ /INR)(P<0.001),while the patients carrying AC genotype had a higher mean warfarin dose than those carrying CC genotype(1.3211±0.4008mg/INR)(P=0.013),the mean warfarin dose differed significantly among the CYP2C9 1061 genotypes(P<0.001).4.Pearson correlation analysis revealed that warfarin dose was sign- ificantly negatively correlated with age(r=-0.198,P<0.001),and signif- icantly positively correlated with body area(r=0.190,P=0.001),there was no significant difference in warfarin dose between the two sexes by covariance analysis(P>0.05).5.Covariance analysis revealed that when VKORC1-1639 genotype was definite, the mean warfarin dose in CYP2C9 1061AC or CC group were lower than AA group(P<0.001);when CYP2C9 1061 genotype was definite, the mean warfarin dose in VKORC1-1639 AA group were lower than AG or GG group(P<0.001).Conclusion: There might be an association between VKORC1-1639G→A,CYP2C9 1061A→C transformation and a lower warfarin dose, the genotype of VKORC1-1639(AA) might be a cause of Chinese lower warfarin dosage.