基于CYP2C9、VKORC1及CYP4F2基因多态性的华法林给药模型的验证

Validation of CYP2C9,VKORC1 and CYP4F2 gene polymorphism-guided warfarin dosing algorithms

目的:对已发表的4个基于CYP2C9、VKORC1和/或CYP4F2基因多态性的华法林给药模型的准确性进行验证,寻找真正适合中国人的给药模型。方法:选择心脏瓣膜置换术后服用华法林至少3个月的患者,用PCR-基因测序方法确定患者CYP2C9、VKORC1及CYP4F2基因型,收集患者基本信息,并记录华法林的实际维持剂量,将患者信息带入4个剂量模型中得到模型预测剂量,计算预测剂量与实际剂量的差异率(DR)。用SPSS统计软件配对t检验、线性回归方法及Bland-Altman分析,验证模型预测剂量的准确性。结果:包含CYP2C9、VKORC1及CYP4F2三个基因在内的给药模型(模型3和模型4)对华法林剂量的预测的DR较仅有CYP2C9和VKORC122个基因的给药模型(模型1和模型2)小,预测剂量与实际剂量的线性回归相关系数高,准确性较高,临床可接受度较高。4个模型对中高等剂量(≥3.00mg·d-1)的预测准确性较好,然而除了模型1外,其他3个模型对极低剂量(≤1.5 mg·d-1)的预测准确性较差。结论:基于CYP2C9、VKORC1及CYP4F2基因多态性的给药模型可以较为准确地预测华法林的给药剂量,但对剂量≤1.5 mg·d-1的预测准确性较差,模型的临床应用有待进一步研究来证实。

OBJECTIVE To validate the accuracy of the four warfarin dosing algorithms based on CYP2CX）, VKORC1 and / or CYP4F2 gene polymorphisms which had published, and find the model which fits Chinese patients best. METHODS Pa tients undergoing heart valve replacement and taking warfarin for at least 3 months were selected. Their basic information and actual maintenance dose of warfarin was collected, and genotypes of CYP2Cg, VKORC1 and CYP4F2 were identified with PCR-sequencing. Subjects informations were applied into our four warfarin dosing algorithms to obtain the predicted dose, calculate the difference-rate （DR） between actual doses and predicted one. Paired t-test, linear regression method and Bland-Ah man analysis of SPSS statistical software were used to verify the accuracy of the predicted dose of each model. RESULTS Models which include three genes-CYP2C9, VKORC1 and CYP4F2 （Models 3 and Model 4） showed a smaller DR and higher R2 compared to Model I and Model 2 which only include CYP2C9 and VKORC1, which means that they had a more accurate predicted results and higher consistency of the clinical work. The prediction accuracy was better in moderate to high dose （≥3.0 mg.d -1 ）. However, the correlation was weaker in low dose condition（≥1. 5 mg.d-1） for each model except Model 1. CONCLUSION The dose algorithms based on CYP2C9, VKORC1 and CYP4F2 gene polymorphism have higher accuracy and consistency than the other ones. However, the accuracy of low dose group needs to be improved, and more data of those groups is needed for further confirmation.