| BackgroundWarfarin is the most widely used oral anticoagulation to avoid thromboembolic events for patients with prosthetic heart valves, atrial fibrillation, pulmonary or venous thromboembolism. However, warfarin therapy is challenging because it has a narrow therapeutic index and dosing requirement vary widely among patients. It has been demonstrated that a significant amount of inter-patient dosing variability can be explained by genotypes for cytochrome P450isoenzyme2C9(CYP2C9) and vitamin K epoxide reductase complex subunit1(VKORC1). Recently, GGCX, PROC, EPHX1, CYP4F2polymorphisms are also reported to relate with warfarin dose variation.However, there is little information about the relationship of GGCX, PROC, EPHX1, CYP4F2polymorphisms with warfarin dose variation in Chinese Han Population. We investigated the effect of VKORC1,CYP2C9, GGCX, PROC, EPHX1andCYP4F2polymorphisms on war farin dose variation,and developed an algorithm to predict the warfarin maintenance dose in Chinese Han Population.Part1:The Impact of Multiple Gene Polymorphisms on Warfarin Maintenance Dose Variation in Chinese Han PopulationObjectivesTo evaluate the impact of VKORC1,CYP2C9, GGCX, PROC, EPHX1and CYP4F2polymorphisms on warfarin maintenance dose variation in Chinese Han Population.Methods1. Subjects:488patients with prosthetic heart valves, atrial fibrillation or pulmonary thromboembolism were enrolled who had achieved stable warfarin dose;2. We detected VKORC1, CYP2C9, GGCX, PROC, EPHX1and CYP4F2polymorphisms,and recorded the demographic characteristics, the stable therapeutic dose of warfarin and concomitant medications of all488patients;3. Methods for genotyping:TaqMan Probe and direct seguencing;4. Analysis the effect of VKORC1, CYP2C9, GGCX, PROC, EPHX1and CYP4F2polymorphisms, demographic factors and concomitant medications on warfarin maintenance daily dose by statistical method.Results1. VKORC1and CYP2C9polymorphisms could explain more than50%warfarin maintenance dose variation in Chinese Han Population, whose impact are larger than demographic factors and concomitant medications.2. CYP4F2polymorphisms could explain only1%warfarin maintenance dose variation in Chinese Han Population..3. GGCX, PROC and EPHX1polymorphisms are not associated with warfarin maintenance dose in Chinese Han Population.Part2:Create a Warfarin Maintenance Dose Algorithm and ValidationObjectivesTo develope a warfarin maintenance dose algorithm for Chinese patients with prosthetic heart valves, atrial fibrillation or pulmonary thromboembolism and validated the accuracy of the algorithm.Methods1. Subjects:All488patients enrolled were divided into derivation group(n=323) and validation group (n=165);2. Create a warfarin maintenance dose algorithm that based on genetic information, demographic factors and concomitant medications in derivation group by multiple linear regression;3. In the validation group,we predicted the warfarin maintenance dose by our algorithm,and evaluated the accuracy of our algorithm by comparing the predicted dose with the actual dose;4. Compare the accuracy of our algorithm with IWPC recommended algorithm.Results1. The warfarin maintenance daily dose algorithm for Chinese patients: Dose(mg)=1.087+2.226×VKORC1-1639AG+3.844×VKORCl-1639GG-1.284×CYP2C9*1/*3-2.182xCYP2C9*3/*3-0.018×age(yr)+0.013×Weight(kg)+0.015×Height(cm)-0.777×Amiodarone-0.379×Digoxin+0.221×CYP4F2CT+0.336×CYP4F2TT R2=0.652,P<0.0012. In the validation group, the predicted dose of our algorithm had no difference with the actual dose (3.51±1.03mg vs3.53±1.41mg, P=0.779), and our algorithm identified60.6%patients whose predicted dose of warfarin was within20%of the actual therapeutic dose.3. In the validation group, the predicted dose of IWPC algorithm was lower than actual dose (3.10±0.83mgvs3.53±1.41mg, P=0.001), and IWPC algorithm identified52.7%patients whose predicted warfarin dose was ideal, but the percentageof underestimation was higher than our algorithm (32.7%vs17.6%, P=0.001)Conclusion1. VKORC1and CYP2C9polymorphisms can be used as bio-markers to predict warfarin maintenance dose in Chinese Han Population.2. The influence of VKORC1gene polymorphisms on warfarin maintenance dose in Chinese Han Population is bigger than CYP2C9gene polymorphism3. CYP4F2polymorphisms could explain only1%warfarin maintenance dose variation in Chinese Han Population..4. GGCX, PROC and EPHX1polymorphisms are not associated with warfarin maintenance dose in Chinese Han Population.5. Our algorithm has the clinical value to predict the warfarin maintena nee dose in Chinese Han Population.6. The accuracy of our algorithm is more than60%in Chinese Han Population and is more accurately than IWPC algorithm...
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