| 摘要: |
| 目的 探讨上海地区汉族人群中细胞色素氧化酶P450 2C9(CYP2C9)、维生素K环氧化物还原酶复合体1(VKORC1)基因多态性对华法林稳定剂量及华法林血浆浓度的影响。方法 纳入在体外循环下行瓣膜置换术且术后需服用华法林抗凝的患者226例,采用焦磷酸测序及UPLC/MS-MS法分别检测其CYP2C9和VKORC1基因型及其华法林血浆总浓度及游离浓度,分别以基因型、性别、年龄进行分组,比较不同组别患者华法林维持剂量和血浆浓度,并计算基因多态性及血药浓度、性别、年龄对华法林稳定剂量的贡献率。结果 CYP2C9(1061A/C)基因型中,AA型患者华法林维持量高于AC型(P<0.05);VKORC1(-1639G/A)基因型中,AG型患者华法林维持量高于AA型患者(P<0.01);VKORC1(1173C/T)基因型中, CT型患者华法林维持量高于TT型患者(P<0.01)。CYP2C9(1061A/C)不同基因型间其华法林血浆浓度差异无统计学意义,VKORC1(-1639G/A)不同基因型间及VKORC1(1173C/T)不同基因型间华法林血浆浓度差异有统计学意义(P<0.01)。男性患者所需华法林维持量高于女性患者(P<0.05),60岁以上患者所需华法林维持量低于60岁以下患者(P<0.05)。CYP2C9(1061A/C)、VKORC1(-1639G/A)、VKORC1(1173C/T)基因多态性及华法林血药浓度、年龄、性别分别解释了7.2%、29.1%、30.4%、6.7%、1.6%和1.4%的华法林个体剂量差异,多因素联合可解释47.2%的华法林个体剂量差异。结论 CYP2C9基因多态性与华法林抗凝药物剂量的个体间差异有关;VKORC1基因多态性与华法林抗凝药物剂量的个体间差异有关,且与其血药浓度密切相关。年龄和性别是影响华法林维持量的重要非基因因素。 |
| 关键词: 华法林 基因多态性 VKORC1 CYP2C9 血药浓度 |
| DOI：10.16781/j.0258-879x.2016.05.0640 |
| 投稿时间：2015-09-07修订日期：2015-12-10 |
| 基金项目:上海市优秀学科带头人计划(12XD1400300),上海市卫生与计划生育委员会青年项目(2012Y137). |
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| Effect of CYP2C9 and VKORC1 gene polymorphisms on warfarin anticoagulation |
| XUE Qian1,LI Wei1,ZHANG Yu-feng1,KANG Bo1,XIAO Jian1,CHEN Wan-sheng2,WANG Zhi-nong1* |
(1. Department of Cardiothoracic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China;
2. Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
*Corresponding author) |
| Abstract: |
| Objective To evaluate the effect of gene polymorphisms in cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) on warfarin maintenance dose and plasma concentration in Chinese Han population in Shanghai. Methods A total of 226 patients who underwent oral warfarin anticoagulation therapy after valve replacement under cardiopulmonary bypass were enrolled in this study. The CYP2C9 1061A/C and VKORC1 -1639 G/A and 1173C/T genotypes were determined by pyrosequencing. The plasma level of warfarin was determined by the UPLC/MS-MS method. The patients were divided into different groups based on genotypes, sex and age. The average daily dose of warfarin and plasma concentration of warfarin were compared between different groups, and the contributions of genotype, plasma concentration, sex and age to warfarin daily dose were calculated. Results Maintenance dose of warfarin in patients with CYP2C9 1061A/C AA type was significantly higher than those with CYP2C9 1061A/C AC type (P<0.05). Maintenance dose of warfarin in patients with VKORC1 -1639G/A AG type was significantly higher than those with VKORC1 -1639G/A AA type (P<0.01). Maintenance dose of warfarin in patients with VKORC1 1173C/T CT type was significantly higher than those with VKORC1 1173C/T TT type (P<0.01). Significant differences of plasma warfarin concentration were also observed between VKORC1 -1639 G/A AA and AG as well as 1173C/T TT and CT genotypes (P<0.01), but not in those with CYP2C9 1061A/C genotypes. The average daily dose of warfarin was significantly higher in male patients than in females (P<0.05). The maintenance dose of warfarin was also significantly higher in patients under 60 years old than those aged above 60 years (P<0.05). CYP2C9 1061A/C, VKORC1 -1639G/A, and VKORC1 1173C/T gene polymorphisms, plasma concentration, age and gender accounted for 7.2%, 29.1%, 30.4%, 6.7%, 1.6% and 1.4% of warfarin dose variance, respectively; and multi-factor combination accounted for totally 47.2% of warfarin dose variance. Conclusion CYP2C9 1061A/C, VKORC1 -1639 G/A and VKORC1 1173C/T genotypes are associated with lower levels of warfarin dose. VKORC1 -1639G/A and 1173C/T genotypes also have a close relationship with warfarin plasma concentration. Sex and age are the important non-genetic influencing factors on warfarin daily dose. |
| Key words: warfarin gene polymorphism VKORC1 CYP2C9 plasma concentration |
