Association Between CYP2C9and VKORC1Polymorphisms With Warfarin Maintenance Dosage After Mechanical Heart Valve Replacement

Objectives The lifelong anticoagulation was conducted after mechanical heart valvereplacement.Warfarin was the preferred oral anticoagulation for mechanical heartvalve replacement. Recent studies had found that cytochrome P4502C9（CYP2C9）and vitamin K epoxide reductase（VKORC1） gene mutation was the most importantgenetic factors that caused individual differences in warfarin. This study sought todetermine the contribution of CYP2C9*3（1075A>C）and VKORC1-1639G>A genesin Chinese Han population. The aim was to explore the association betweennon-genetic factors genetic factors,including age,gender,body mass index（BMI）,andCYP2C9or VKORC1gene variants with warfarin maintenance dosage in ChineseHan population. The study was to investigate the effects of non-genetic factorsgenetic factors,including age, gender, body mass index（BMI）and CYP2C9orVKORC1gene on warfarin maintenance dosage in patients after mechanical heartvalve replacement,so as to provide the basis for individualize warfarin dosage aftermechanical heart valve replacement in Chinese Han population.Methods One hundred seventy-nine patients in Shanxi Han population on stableanticoagulation with a target International Normalized Ratio (INR) of1.7to3.0wererecruited,including145patients with mechanical heart valve replacement （130patients administrated oral imports warfarin）.One hundred and fifty healthyindividuals were as the controls.The CYP2C9*3（1075A>C）and VKORC1-1639G>Agenotype were detested by amplification refractory mutation-polymerase chainreaction (ARMS-PCR).Gene frequency distribution were compared between patientsand healthy subjects. Age,gender,BMI, different genotypes of CYP2C9*3(1075A>C)and VKORC1-1639G>A with warfarin maintenance dosage were observed in patientsadministrated oral warfarin. Further130patients administrated oral imports warfarin after mechanical heart valve replacement be analyzed by multiple linear regressionanalysis method,and the prediction model of warfarin maintenance dosage aftermechanical heart valve replacement was established.Results（1）There was no difference in single nucleotide polymorphism (SNP)contribution of CYP2C9*3(1075A> C)and VKORC1-1639G> A between normalsubjects and patients.Among329cases enrolled,CYP2C9*(1075A>C)AA,AC andCC genotype frequencies were89.1%,10.0%,0.9%,while the frequency of allele Aand C were94.1%and5.9%,respectively.VKORC1-1639G> A GG, GA, AA genotypefrequency were0,15.5%and84.5%,while G and A allele frequencies were7.7%and92.3%, respectively.（2）Among179cases enrolled,the warfarin maintenance dosage in CYP2C9*3(1075A>C) AC+CC group was (2.35±1.13) mg/d,which was significantly reducedcompared with AA group (2.92mg/d±1.11） mg/d,（P=0.045<0.05).The warfarinmaintenance dosage in VKORC1-1639G>AAA group wa（s2.72±1.00） mg/d,whichwas significantly reduced compared with GA group (3.84mg/d±1.46mg/d，P=0.013<0.05).Age was negatively correlated with warfarin maintenance dosage(r=-0.186，P=0.013<0.05).There is no correlation between gender and BMI withwarfarin maintenance dosage (P=0.087>0.05vs P=0.923>0.05).（3）The regression equation of warfarin maintenance dosage after mechanical heartvalve replacement was established based on the multiple linear regression method:y=1.483-0.435×VKORC1-0.386×CYP2C9-0.127×gender (Y is the logarithmic ofaverage dose). The multiple linear regression analysis revealed that there is nocorrelation between age and BMI with warfarin maintenance dosage (P>0.05) whilethere is correlation between VKORC1-1639G>A, CYP2C9*3(1075A>C) and genderwith warfarin maintenance dosage（P<0.05)，which could explain6%，6%,3%ofindividual warfarin variation.The standardized coefficients were-0.329,-0.329,-0.160,multiple factors jointly accounted for19.1%of individual warfarin variation.Conclusion （1）There was no difference in the distribution of CYP2C9*3（1075A>C）and VKORC1-1639G>A between healthy individuals and medication patients in Chinese Han population. There was no racial differences in CYP2C9*3(1075A>C)genotype while there was racial differences in VKORC1(-1639G> A) genotype withmutation AA type mainly in Chinese Han population.（2）With regard to difference in the correlation of age and gender in differentselected populations with warfarin maintenance dosage,it considered that there weremore confounding factors while sample did not increase in179patients.Patientsadministrated oral imports warfarin after mechanical heart valve replacement hadmajority and sample homogeneity of the enrolled patients,so its results is morereliable,as the final result.The warfarin maintenance dosage in women aftermechanical heart valve replacement was lower than that in men.The warfarinmaintenance dosage in CYP2C9*3(1075A>C) AC,CC genotype was lower than AAgenotype while that in VKORC1-1639G>A AA genotype was lower than GAgenotype.（3）Although the prediction model established in this study only explain19.1%ofindividual warfarin variation,but as a reference method,it can guide patientspersonalized medicine, in order to avoid the blindness of the medication.