基因型指导我国汉族人群华法林稳定治疗剂量预测模型的验证及评价
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篇名: 基因型指导我国汉族人群华法林稳定治疗剂量预测模型的验证及评价
TITLE:
摘要: 目的:验证并评价4种华法林药物基因组学稳定治疗剂量预测模型在我国汉族人口中应用的准确性。方法:选择口服华法林抗凝治疗达稳定治疗剂量的患者140例及同期健康受试者94例,应用基因芯片法检测其CYP2C9及VKORC1的基因多态性,分析所有受试者基因型分布特征,并考察不同基因型患者实际稳定治疗剂量间的差异;结合IWPC、Gage、Huang、Miao剂量预测模型公式计算华法林预测剂量,考察其与实际稳定治疗剂量间的相关性,并评价各模型预测的准确性。结果:234例受试者的CYP2C9、VKORC1基因频率符合Hardy-Weinberg平衡。140例患者中,CYP2C9*1/*1型患者实际稳定治疗剂量高于*1/*3型患者,差异有统计学意义(P<0.001);VKORC1 AA型患者实际稳定治疗剂量低于GA型及GG型患者,差异有统计学意义(P<0.001)。IWPC、Gage、Huang、Miao模型预测剂量均与实际稳定治疗剂量相关(R2分别为0.701、0.166、0.664、0.605,P均<0.001)。当实际稳定治疗剂量≤2.5 mg/d时,4种模型预测剂量与实际稳定治疗剂量间的差异均有统计学意义(P均<0.05);当实际稳定治疗剂量为>2.5~<5 mg/d时,Gage、Huang、Miao模型预测剂量与实际稳定治疗剂量间的差异有统计学意义(P均<0.05),而IWPC模型预测剂量与实际稳定治疗剂量间的差异无统计学意义(P>0.05);当实际稳定治疗剂量≥5 mg/d时,Huang、Miao模型预测剂量与实际稳定治疗剂量间的差异有统计学意义(P均<0.05),而IWPC、Gage模型预测剂量与实际稳定治疗剂量间的差异无统计学意义(P均>0.05)。结论:CYP2C9和VKORC1不同基因型患者华法林实际稳定治疗剂量个体差异显著;IWPC模型对稳定治疗剂量在>2.5~<5 mg/d范围内的患者有较好的预测作用,对临床提高华法林抗凝治疗的安全性和有效性具有潜在的意义。
ABSTRACT: OBJECTIVE: To validate and evaluate the accuracy of 4 kinds of warfarin genomics maintenance dose prediction model of in Chinese patients. METHODS: 140 patients receiving oral warfarin anticoagulant therapy to keep maintenance dose and 94 healthy volunteers were selected. CYP2C9 and VKORC1 gene polymorphism were detected by gene chip. The characteristics of genotype distribution were analyzed, and the difference of practical maintenance dose were investigated among different genotype patients. The dose of warfarin was calculated by using IWPC, Gage, Huang and Miao dose prediction model. The relationship of warfarin dose with practical maintenance dose was investigated, and the accuracy of prediction model was evaluated. RESULTS: CYP2C9 and VKORC1 gene frequency of 234 volunteers were in line with Hardy-Weinberg balance. Of 140 patients, actual maintenance dose in CYP2C9*1/*1 genotype was higher than in CYP2C9*1/*3 genotype, with statistical significance (P<0.001); actual maintenance dose in VKORC1 AA genotype was lower than in GA and GG genotype, with statistical significance (P<0.001). IWPC, Gage, Huang and Miao dose prediction models were correlated with actual maintenance dose (R2=0.701, 0.166, 0.664 and 0.605, all P<0.001). When actual maintenance dose ≤2.5 mg/d, there was statistical significance between 4 dose prediction models and actual dose (all P<0.05); when actual maintenance dose ranged >2.5-<5 mg/d, there was statistical significance between Gage, Huang and Miao dose prediction models and actual dose (all P<0.05); there was no statistical significance between IWPC dose prediction model and actual dose (P>0.05); when actual maintenance dose≥5 mg/d, there was statistical significance between Huang and Miao model and actual dose (all P<0.05); there was no statistical significance between IWPC and Gage model and actual dose (all P>0.05). CONCLUSIONS: There is significant difference in actual maintenance dose between CYP2C9 genotype and VKORC1 genotype; IWPC model can predict the dose of warfarin in patients with maintenance dose of >2.5-<5 mg/d well, which is of potential significance to safety and effectiveness improvement of warfarin anticoagulant therapy.
期刊: 2016年第27卷第11期
作者: 管文燕,徐航,叶庆
AUTHORS: GUAN Wenyan,XU Hang,YE Qing
关键字: 华法林;CYP2C9;VKORC1;基因多态性;剂量预测模型;验证
KEYWORDS: Warfarin; CYP2C9; VKORC1; Gene polymorphism; Dose prediction model; Validate
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