Effects Of CYP2C9and VKORC1Genetic Polymorphisms On Response To Stable Warfarin Dose In Patients With Heart Valve Replacement

ObjectiveTo explore the distribution of Cytochrome P450(CYP2C9*31075A/C) andVitamin-K epoxide reductase complex1(VKORC1-1639G/A) in Han population inFujian Province. Application of genetic polymorphisms to estimate the stable warfarindose in heart valve replacement patients concomitant Calcium ChannelBlockers(CCBs).MethodsA total of146patients with heart valve replacement were attending clinics atFujian provincial hospital and prescribed warfarin with stabilized INR in1.5–2.5wereselected. Two groups:70patients concomitant calcium channel blockers;76patientswithout calcium channel blockers. DNA microarray (gene chip) method was used toevaluate the genotypes of CYP2C9*31075A/C and CKORC1-1639G/A. Andcompare stable therapeutic doses between the CYP2C9and VKORC1genotypegroups. Lastly, our model based on the combination of genetic and clinical variablesis available to guide clinical treatment.Results1.Two groups:70patients concomitant calcium channel blockers (47.9%)；76patients without calcium channel blockers（52.1%）. There was not significantdifference between two groups for patients’ demographics（P＞0.05）. Daily averagewarfarin dose of patients with CCBs was significantly below the patients setting freeCCBs (2.95±1.16mg VS3.41±1.14mg,P=0.015).2.The mean warfarin daily dose required was2.58±1.19mg in CYP2C9*3ACpatients,which was significantly lower than3.27±1.15mg in homozygous wildtype(P=0.026).The VKORC1-1639AA genotype patients received significantly lower doses of warfarin than those with GA and GG genotype(2.85±0.81mg VS4.23±1.18mg VS6.50±2.17mg, P＜0.01).3.The model (R2=46.4%) is following as Dose=1.80-0.95CYP2C9+1.56VKORC1+0.34CCB(CYP2C9*3AA=1/AC=2, VKORC1-1639AA=1/GA=2/GG=3, Concomitant CCBs=1, Without CCBs=2).Conlusions1.We used DNA microarray (gene chip) method to evaluate the genotypes ofCYP2C9*31075A/C and CKORC1-1639G/A, the genotype frequencies of146patients are basically identaical with other studies on Asians distribution.2.Application of pharmacogenetics to assess the stable warfarin dose in heartvalve replacement patients concomitant calcium channel blockers. We may guideindividualized treatment to prevent patients from being over or undercoagulated.