CYP2C9和VKORC1基因多态性对华法林稳态治疗剂量及个体化抗凝疗效的影响  

Effect of CYP2C9 and VKORC1 gene polymorphism on warfarin steady-state therapeutic dose and individual anticoagulation efficacy

作　　者：寇惠娟[1] 邓捷 朱参战[1] 李永勤[1] 马瑞[1] 张岩[1] 张春艳[1] 郑强荪 

机构地区：[1]西安交通大学第二附属医院心内科,西安710004

出　　处：《山西医科大学学报》2017年第11期1102-1107,共6页Journal of Shanxi Medical University

基　　金：中央高校基本科研业务费资助项目(0817-1191320079);西安交通大学第二附属医院科技新苗基金资助项目(RC(XM)201608);西安交通大学第二附属医院青年科研基金资助项目(YJ(QN)201419)

摘　　要：目的探讨非瓣膜病房颤患者华法林CYP2C9和VKORC1基因多态性对药物稳态治疗剂量及个体化抗凝疗效的影响。方法收集2015-06~2017-03在西安交通大学第二附属医院心内科门诊及住院的非瓣膜病房颤患者,应用CHA2DS2-VASc和HAS-BLED评分系统进行评估。将接受口服抗凝治疗患者分为传统对照组(从小剂量1.5-3.0 mg/d开始的传统给药方案)和个体化治疗组(采用国际权威推荐的华法林个体化剂量预测模型计算华法林初始抗凝治疗剂量),进行华法林CYP2C9和VKORC1基因多态性检测,监测国际标准化比值(INR),计算服药后INR达标时间,观察华法林稳态治疗剂量与初始推荐治疗剂量的相关性,以及药物相关不良事件发生。结果共纳入非瓣膜病房颤患者678例,134例患者接受口服华法林抗凝药物治疗方案,约占19.8%。传统对照组(n=65)和个体化治疗组(n=69)患者在年龄(P=0.016)、华法林初始推荐治疗剂量(P<0.001)和达标时间(P<0.001)方面差异具有统计学意义,随访期间均未观察到药物相关不良事件的发生。CYP2C9*2(R144C,C>T)野生CC型,杂合突变CT型和纯合突变TT型分别为100%,0%和0%;CYP2C9*3(I359L,A>C)野生AA型,杂合突变AC型和纯合突变CC型分别为95.7%,4.3%和0%;VKORC1(1639,G>A)野生GG型,杂合突变GA型和纯合突变AA型分别为0%,17.4%和82.6%。计算的华法林推荐治疗剂量CYP2C9*2 CC型为(3.24±0.91)mg/d,CYP2C9*3 AA型和AC型分别为(3.31±0.90)mg/d和(2.24±0.16)mg/d,VKORC1 GA型和AA型分别为(3.81±1.34)mg/d和(3.10±0.75)mg/d。线性相关分析显示华法林稳态治疗剂量与年龄呈显著负相关(r=-0.589,P<0.001),与身高(r=0.384,P=0.033)和基于公式计算的华法林初始推荐治疗剂量(r=0.935,P<0.001)呈显著正相关。多元线性回归分析结果显示,年龄、CYP2C9*3和VKORC1是华法林推荐治疗剂量的独立影响因素。两组患者均未观察到药物相关血栓栓塞及出血事件的发生。结论在非瓣膜病房�Objective To explore the effect of CYP2 C9 and VKORC1 gene polymorphism on warfarin steady-state therapeutic dose and individual anticoagulation therapy in patients with non-valvular atrial fibrillation. Methods The subjects with non-valvular atrial fibrillation were enrolled from cardiovascular clinic and in-patient wards from June 2015 to March 2017. After using the CHA2 DS2-VASc and HAS-BLED system to evaluate the risks of stroke and bleeding,the patients with oral anticoagulant therapy were divided into conventional group（ initial dose of 1. 5-3. 0 mg/d） and individual group（ the individualized recommended treatment dose of warfarin based on CYP2 C9 and VKORC1 genotyping）. The genotype and allele frequency of CYP2 C9 and VKORC1,the time required for INR 2. 0-3. 0 after taking warfarin,association between individualized recommended treatment dose and warfarin steady-state therapeutic dose,and the incidence of drug-related side effects in individual group and conventional group were explored in the clinical study. All data were analyzed using SPSS 13. 0 software. Results A total of 678 participants were enrolled into the study,and 134 patients received the oral anticoagulant therapy finally. The age（ P = 0. 016）,individualized recommended treatment dose（ P 0. 001） and the time required for INR 2. 0-3. 0 after taking warfarin（ P 0. 001） were significantly different between individual group and conventional group. The CYP2 C9＊ 2（ R144 C,C T） genotyping showed that the allele frequencies of CC,CT and TT were 100%,0% and 0%,respectively. CYP2 C9＊ 3（ I359 L,A C） genotyping showed that the allele frequencies of AA,AC and CC were 95. 7%,4. 3% and0%,respectively. VKORC1（ 1639,G A） genotyping showed that the allele frequencies of GG,GA and AA were 0%,17. 4% and82. 6%,respectively. The warfarin dose was（ 3. 24 ± 0. 91） mg/d in CYP2 C9＊ 2 CC,（ 3. 31 ± 0. 90） mg/d and（ 2. 24 ± 0. 16） mg/d in CYP2 C9＊ 3-I359 L AA and AC,（ 3. 81 ± 1. 34） mg/d and（ 3. 10 ± 0. 75�

关 键 词：华法林 房颤 CYP2C9基因型 VKORC1基因型 抗凝治疗 

分 类 号：R541.7[医药卫生—心血管疾病]