汉族人心脏瓣膜置换术后华法林用药剂量与基因型关系的相关性研究  

Correlation of Warfarin Dosage and Genetic Polymorphism of Han-patients after Heart Valve Replacement

作　　者：王玉庆[1,2] 董力[1] 石应康[1] 侯江龙[1] 江虹[3] 付博[1] 

机构地区：[1]四川大学华西医院心脏大血管外科,成都610041 [2]济南市第三人民医院胸外科,济南250132 [3]四川大学华西医院检验科,成都610041

出　　处：《中国胸心血管外科临床杂志》2016年第1期1-6,共6页Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

基　　金："十二五"国家科技支撑计划项目(2011BAI11B18);四川省科技厅科技支撑计划项目(2009SZ0207)~~

摘　　要：目的探讨汉族人心脏瓣膜置换术后抗凝治疗华法林用药剂量个体差异与其基因多态性的相关性,预测患者华法林抗凝治疗的合理用药剂量,实现抗凝监测的个体化管理。方法选择《中国人心脏瓣膜置换术后抗凝治疗数据库》中2011年1月1日至2012年12月31日在四川大学华西医院接受心脏瓣膜置换术、术后服用华法林行抗凝治疗,并接受国际标准化比值（international normalized ratio,INR）行抗凝监测的患者103例。其中男32例、女71例,年龄21~85（48.64±11.66）岁,采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法和基因测序技术检测CYP2C9（rs1057910）和VKORC1（rs9923231）基因位点的基因型和等位基因频率。用超高效液相色谱法（HPLC）检测患者华法林血药浓度,并用Sysmex CA7000 analyser试剂盒检测其凝血因子Ⅱ、Ⅶ、Ⅸ、Ⅹ活性。结果性别、体表面积和凝血因子活性对华法林用药剂量的影响相对较弱。CYP2C9＊3、VKORC1-1639、华法林血药浓度以及年龄对华法林用药剂量的影响相对较强,其影响程度（r2）依次为1.2%、26.5%、43.4%和5.0%。并由此推导出回归方程：Y=1.963-0.986×（CYP2C9＊3）＋0.893×（VKORC1-1639）＋0.002×（华法林血药浓度）-0.019×（年龄）。结论结合CYP2C9和VKORC1两种基因的多态性检测结果、华法林血药浓度、年龄等非遗传因素建立的多元回归方程,可预测患者华法林抗凝治疗的合理用药剂量,从而实现抗凝监测的个体化管理,减少其并发症的发生。Objectives To investigate the correlation of warfarin dose genetic and polymorphism of Han-patients after heart valve replacement, to forecast the anticoagulation therapy with warfarin reasonable dosage, and to realize individualized management of anticoagulation monitoring. Methods We selected 103 patients between January 1, 2011 and December 31, 2012 in West China Hospital of Sichuan University who were treated by oral warfarin after heart valve replacement with monitoring anticoagulation by international normalized ratio（INR） in Anticoagulation Therapy Database of Chinese Patients after Heart Valve Replacement. There were 32 males and 71 female at age of 21-85（48.64 ±11.66） years.All the patients＇ CYP2C9 and VKORC1 genetic polymorphisms were detected by using polymerase chain reaction-restriction fragment length polymorphism（PCR-RELP） method and gene sequencing technology. Warfarin concentration in plasma was determined by high performance liquid chromatography（HPLC） method. The activity of coagulation factor Ⅱ, Ⅶ,Ⅸ, Ⅹ was determined by Sysmex CA7000 analyzer. Results The multivariate linear regression analysis showed that age,body surface area, and coagulation factor activity had no significant effect on warfarin dosage. While the gene polymorphisms of CYP2C9 and VKORC1, warfarin concentration, and age had significant contributions to the overall variability in warfarin dose with decisive coefficients at 1.2%, 26.5%, 43.4%, and 5.0% respectively. The final equation was： Y=1.963-0.986×（CYP2C9＊3） ＋0.893×（VKORC1-1639） ＋0.002×（warfarin concentration）- 0.019×（age）. Conclusion Multiple regression equation including gene polymorphisms of CYP2C9 and VKORC1, non-genetic factors of coagulation factor activity, warfarin concentration, age, and body surface area can predict reasonable dosage of warfarin for anticoagulation to achieve individualized management of anticoagulation monitoring and reduce the anticoagulation complications.

关 键 词：心脏瓣膜置换术 抗凝治疗 华法林 基因多态性 

分 类 号：R654.2[医药卫生—外科学]