中国患者华法林抗凝治疗剂量的药物基因组学相关性及药物基因组学方程的比较分析

目的药物基因组学方程对华法林剂量的预测作用的重要性日益受到重视。但是，其准确性仍受到种族和包括华法林剂量在内的多种临床因素的影响。本文旨在接受低剂量华法林抗凝治疗的中国患者中，验证遗传因素对华法林治疗剂量的影响，并分析药物基因组学方程对华法林不同剂量范围的预测效果。方法在接受低强度华法林抗凝治疗（目标INR为1．6～2．5）的中国患者队列（n=282）人群中，检测CYP2C93、VKORC1-1639A／G和CYP4F2＊3基因多态性与华法林稳定治疗剂量的关系。根据华法林剂量将患者分为低剂量组（≤1．5mg／d），中间剂量组（1．5～4．5mg／d）和高剂量组（≥4．5mg／d），分别评估8个药物基因组学方程在各组患者中的预测效果。预测效果评估指标包括，剂量预测值位于实际值20％界限内的患者比例（20％内患者比例），预测值与实际值之间绝对误差的平均值（MAE）。结果华法林的稳定治疗剂量在各个基因的变异基因型携带者和野生基因型携带者之间均存在显著差异（CYP2C9-3：P〈0．00l；VKORC1-1639A／G：P〈0．001；CYP4F2＊3：P=0．025）。来自白种人群和混合人群的药物基因组学方程在华法林高剂量组中预测效果最好，而来自亚洲人群的方程在中间剂量组中的预测效果更好。所有方程对低剂量患者的剂量预测效果均不佳。结论CYP2C93、VKORC1-1639A／G和CYP4F2＊3基因多态性均与中国人群华法林稳定治疗剂量相关。已有的药物基因组学方程尚不能有效的预测华法林各个剂量组患者的稳定治疗剂量。

Pharmacogenetic association and predictive accuracy of pharmacogenetic algorithms in Chinese patients under warfarin anticoagulation

Objective The importance of pharmacogenetic algorithms in warfarin dose prediction has drawn more attention. However, their performance has still been influenced by race and multiple clinical factors including warfarin dosage. The aim of this study was to evaluate the relationship of warfarin dosage with polymorphisms of CYP2C93, VKORCl-1639 A/G and CYP4F2＊3, and the accuracy ofpharmacogenetic algorithms. Methods We detected the polymorphisms ofCYP2C9＊3,VKORCI-1639 A/G and CYP4F2＊3 in a cohort of Chinese patients （n = 282） under low intensity warfarin anticoagulation with target inte ational normalized ratio （INR） ranging from 1.6 to 2.5, and evaluated the relationship between warfarin dosage and these polymorphisms. Then, the patients were stratified to 3 groups according to the dose range： higher dose group （t〉4.5 mg/d）, intermediate dose group （1.5-4.5 mg/d）, and lower dose group （≤ 1.5 mg/d）. We evaluated the performances of 8 eligible pharmacogenetic algorithms in different dose range. The performance of each algorithm was evaluated by calculating the percentage of patients whose predicted dose fell within 20% of their actual therapeutic dose （percentage within 20%）, and the mean absolute error （MAE） between each predicted dose and actual stable dose. Results In the entire cohort, warfarin doses differed significantly across genotypes for CYP2C93 （P〈 0.001）, VKORCl-1639 A/G （P 〈 0.001）, and CYP4F2＊3 （P = 0.025）. The algorithms from Caucasian and racially mixed populations tended to perform better in higher dose group, and algorithms from Asian populations performed better in intermediate dose group. None of the algorithms performed well in lower dose group. Conclusions Polymorphisms of CYP2C93, VKORCl-1639 A/G and CYP4F2＊3 associate with stable warfarin dose in Chinese patients. No eligible pharmacogenetic algorithm could perform satisfactorily for all dosing range in the Chinese patients.