细胞色素氧化酶P4502C9以及维生素K环氧化物还原酶复合体1基因多态性对华法林抗凝疗效的影响

Association between CYP2C9 and VKORC1 genetic polymorphism and warfarin dose requirements

目的研究年龄、体重、身高、体表面积、细胞色素氧化酶P450（CYP2C9）和维生素K环氧化物还原酶复合体1（VKORC1）基因型与华法林剂量的关系。方法收集临床使用华法林的患者共191例，记录患者的年龄、性别、身高、体重等。利用聚合酶链反应（PCR）和限制性内切酶片段长度多态性（RFLP）技术检测CYP2C9以及VKORC1基因型。结果VKORC1（-1639G〉A）基因型检测有159例患者为突变纯合子AA型，31例患者为杂合子GA型，1例患者为纯合子GG型。CYP2C9基因型检测有176例患者为＊1／＊1型，15例患者为杂合子＊1／＊3型。VKORC1（-1639G〉A）GA＋GG组，华法林平均剂量明显高于AA组[（3．36±0．97）mg／d比（1．75±0．56）mg／d，P〈0．01]。CYP2C9＊1／＊1型患者华法林平均剂量高于杂合子＊1／＊3型患者[（2．06±0．83）mg／d比（1．55±1．32）mg／d，P〈0．05]。多元线形回归分析提示年龄、体重以及VKORC1基因型分别解释了约9．3％、7．4％、51．9％的个体间剂量差异，包括年龄、体重、VKORC1和CYP2C9基因型的多变量模型能解释个体间剂量差异约为64．1％。结论年龄、体重、VKORC1和CYP2C9基因多态性明显影响了华法林剂量。用年龄、体重、VKORC1和CYP2C9基因型的多变量模型给药方法希望提高华法林使用的安全性。

Objective To assess the contribution of vitamin K epoxide reductase complex 1 （VKORC1） and cytochrome P450 2C9（CYP2C9） genotype, age, body size, height, and weight to warfarin dose requirement. Methods Blood samples were collected from 191 patients receiving warfarin therapy. Patients＇s age, gender, height, and weight were registered. PCR-RFLP method was used for the detection of VKORC1-1639G 〉 A and CYP2C9 genotype. Results VKORC1-1639G 〉 A genotyping showed that 159 patients were homozygous AA, 31 were heterozygous GA, and 1 was homozygous GG genotype. CYP2C9 genotyping showed that 176 patients were ＊ 1/＊ 1, 15 patients were heterozygous ＊ 1/＊ 3. Patients with VKORCl-1639（ G 〉 A）GG ＋ GA genotype required a significantly higher warfarin dose than those with AA genotype[ （3.36 ± 0. 97） mg/d vs. （ 1.75 ± 0. 56） mg/d, P 〈0. 01], and patients with CYP2C9 ＊ 1/＊ 1 genotype also required a higher warfarin dose than those with CYP2C9 ＊ 1/＊ 3 genotype [ （2. 06 ± 0. 83 ） mg/d vs. （1.55 ± 1.32 ）mg/d, P 〈 0. 05 1. The multiple linear regression model for warfarin dose indicated age, weight and VKORC1 genotype could explain the inter-individual variation in dose requirement of 9.3%, 7.4%, 51.9% patients, respectively; age, weight, CYP2C9 and VKORC1 genotype together could explain the inter-individual variation in dose requirement of 64. 1% patients. Conclusion This study showed that age, weight and VKORC1 and CYP2C9 polymorphism had significant influences on warfarin dose requirements and should be considered on dosing regimens modification to improve the safety of warfarin therapy.