山东人群华法林稳定剂量预测模型的准确性验证

Verification of accuracy of warfarin stable dose prediction models in Shandong population

目的比较5种华法林稳定剂量预测模型以及经验给药方式(2.5 mg/day)对山东人群预测的准确性。方法招募正在或曾经服用华法林并已达到稳定剂量的患者,检测重要的华法林药物代谢基因的型别,收集患者的临床信息,采用预测百分比及绝对误差均值法评价各模型预测的准确性。结果在入组的125例患者中,CYP2C9*1/*1、CYP2C9*1/*3和CYP2C9*1/*2基因型分别占92.00%、7.20%和0.80%。VKORC1-1639 AA、AG、GG基因型分别占82.40%、15.20%、2.40%;CYP4F2*1/*1、*1/*3,*3/*3基因型分别占50.40%、39.20%、10.40%。在其他位点型别固定的情况下,CYP2C9*1/*3和CYP2C9*1/*2基因型个体与CYP2C9*1/*1相比华法林剂量明显降低。VKORC1-1639 AG型与AA型相比华法林稳定剂量增加45%~50%(P<0.05)。CYP4F2*1/*3与CYP4F2*1/*1基因型个体相比,华法林稳定剂量增加约5.9%(P=0.02);CYP4F2*3/*3与CYP4F2*1/*1基因型个体相比华法林剂量增加约13.0%(P=0.129)。预测效果较好的模型包括IWPC(59.20%)、Huang(57.60%)、Ohno(52.80%),绝对误差均值分别为0.35(95%CI:0.11~0.49)、0.15(95%CI:0.10~0.32)、0.39(95%CI:0.12~0.51)。结论CYP2C9、VKORC1、CYP4F2等3个基因的多态性对山东人群的华法林稳定剂量存在影响。IWPC模型更适用于山东人群。

Objective To compare the accuracy of five warfarin-dosing algorithms and warfarin stable dose model(2.5 mg/day)for Shandong population.Methods One hundred and twenty five patients who achieved stable warfarin dose were enrolled.Clinical and genetic data were used to evaluate the value of each algorithm by calculating the percentage of patients whose predicted warfarin dose was within 20%of the actual stable therapeutic dose and mean absolute error(MAE).Results The frequency of patients with CYP2C9*1/*1,CYP2C9*1/*3 and CYP2C9*1/*2 genotype was 92.00%,7.20%,0.80%,respectively.That of VKORC1-1639 AA,AG and GG genotype was 82.40%,15.20%,2.40%,respectively.CYP4F2*1/*1,*1/*3,*3/*3 genotype was 50.40%,39.20%,10.40%,respectively.With the same genotypes for other loci,patients who carried at least one VKORC1-16398G mutant allele had increased warfarin stable daily dose compared with VKORC1-1639AA.Compared with CYP4F2*1/*1,those carrying at least one CYP4F2*3 mutant allele had warfarin stable daily dose increased by 5.9%-13.00%.The percentage of ideal prediction calculated from IWPC model(59.20%),Huang model(57.60%)and Ohno model(52.80%)were higher than others.The MAE were 0.35(95%CI:0.11-0.49),0.15(95%CI:0.10-0.32),0.39(95%CI:0.12-0.51),respectively.Conclusion The polymorphisms of CYP2C9,VKORC1 and CYP4F2 genes can influence the stable dose of warfarin in Shandong population.IWPC algorithm is suitable for guiding the use of warfarin in this population.