Effects Of CYP2C19*2and CYP4F2Genetic Polymorphisms On Maintenance Dose And Steady State Concentration Of Warfarin

Objective：1. To determine the patients’ warfarin concentration by HPLC, analysis therelationship between warfarin concentration and INR.2. Analysis the relationship between the variations of CYP2C19*2and CYP4F2rs2108622and the maintenance dose and steady state concentration of warfarin.Methods:1. To collect blood samples and clinical data from patients of Warfarin.2. To establish HPLC-UV method for detection warfarin concentration, Pearsoncorrelation analysis was used to find out the correlation between warfarinconcentration and INR.3. To establish PCR-RFLP method for detection of genotype of CYP2C19*2andCYP4F2.4. The differences of the maintenance dose and steady state concentration of warfarinfor different genotypes are analyzed by ANOVA one-way test.Results:1. Pearson correlation analysis shows that the relationship between warfarinconcentration and INR was strong (r=0.468, P=0.012), the relationship betweensteady state concentration of warfarin and INR was poor (r=0.081, P=0.416).2. The mutation frequency of CYP2C19*2was36.06%, mutation frequency ofCYP4F2was21.63%.3. For the patients with CYP2C19*1/*1,*1/*2,*2/*2genotype warfarin maintenancedose were3.23±0.94mg/d;3.17±1.18mg/d;3.05±1.22mg/d respectively, showedno significant differences for the three CYP2C19*2genotype (P=0.162); CYP2C19 had no effect within both VKORC1-AA/CYP2C9*1/*1group and VKORC1-AG/CYP2C9*1/*1group. For the patients with CYP2C19*1/*1,*1/*2,*2/*2genotypewarfarin concentration were822.141±337.642ng·mL-1;914.772±398.544ng·mL-1;828.026±483.949ng·mL-1respectively, showed no significant differences for the threegenotype (P=0.338).4. For the patients with CYP4F2CC, CT and TT genotype warfarin maintenance dosewere2.74±0.91mg/d,3.16±0.92mg/d and3.75±1.06mg/d respectively, for thepatients with CC and TT genotype maintenance dose was higher than that of patientswith CC genotype (P=0.022), CYP4F2SNP can explain about6.2%of the variance inwafarin maintenance dose; In VKORC1-AA/CYP2C9*1/*1group, CYP4F2SNP canexplain about10.8%of variance in warfarin maintenance dose, but had no effectwithin VKORC1-AG/CYP2C9*1/*1group. For the patients with CYP4F2CC, CT andTT genotype steady state concentration of warfarin was814.985±365.077ng·mL-1,996.582±347.712ng·mL-1and1040.179±428.150ng·mL-1, for the patients with CCand TT genotype steady state concentration of warfarin was higher than that ofpatients with CC genotype (P=0.044).4. For the patients with CYP2C19*1/*1,*1/*2,*2/*2allele warfarin sensitivity were3.03±1.47；2.70±1.61；3.46±2.09respectively, showed no significant differences forthe three CYP2C19*2genotype (P=0.139).5. For the patients with CYP4F2CT/TT genotype warfarin sensitivity both lower thanthat of patients with CC genotype (2.54±1.76vs.3.21±1.59, P<0.05).Conclusion:1. When INR <1.5, the correlation of warfarin concentration and INR was strong, thecorrelation of steady state concentration of warfarin and INR was poor.2. The SNPs of CYP2C19*2do not affect warfarin maintenance dose and steady stateconcentration of warfarin3. The high dose requirement in those with CT/TT genotype in CYP4F2rs2108622were attributable to low sensitivity of warfarin. Steady state concentration of warfarinin those with CT/TT genotype in CYP4F2was higher than those with CC genotype.