中国汉族人群基于临床特征和基因型华法林个体化给药模型的研究

中国临床药理学与治疗学 ›› 2014, Vol. 19 ›› Issue (3): 284-290.

中国汉族人群基于临床特征和基因型华法林个体化给药模型的研究

刘俊^1,3, 栾家杰^1,3, 徐文科^1,3, 朱艳虹^1,3, 汪魏平^1,3, 张大发²

¹皖南医学院弋矶山医院药剂科, 芜湖 241001,安徽;
²胸心外科, 芜湖 241001,安徽;
³皖南医学院临床药学研究所,芜湖 241001,安徽

收稿日期:2013-12-13 修回日期:2014-02-27 出版日期:2014-03-26 发布日期:2014-04-10
通讯作者: 栾家杰,男,博士,副主任药师,研究方向: 临床药学。Tel: 15855965132 E-mail: luanjiajie757@163.com
作者简介:刘俊,男,本科,主管药师,主要研究方向:临床药学。Tel: 13965172493 E-mail: xiaoyu234561@sina.com
基金资助:
安徽省“十二五”临床重点专科学科建设基金(01Z35);皖南医学院弋矶山医院引进人才科研基金资助项目(YR201204)

Study on warfarin individual dosage model based on clinical factors and gene in Chinese Han population

LIU Jun^1,3, LUAN Jia-jie^1,3, XU Wen-ke^1,3, ZHU Yan-hong^1,3, WANG Wei-ping^1,3, ZHANG Da-fa²

¹Department of Pharmacy,Yijishan Hospital of Wannan Medical College,Wuhu 241001, Anhui,China;
²Department of Cardiothoracic Surgery,Wuhu 241001, Anhui,China;
³Laboratory of Clinical Pharmacy, Wannan Medical College,Wuhu 241001, Anhui,China

Received:2013-12-13 Revised:2014-02-27 Online:2014-03-26 Published:2014-04-10

摘要/Abstract

摘要： 目的: 评价中国汉族人群临床特征及基因型对华法林剂量的影响,并构建华法林给药模型,为临床华法林个体化给药提供参考。方法: 按照设定标准选取某医院2011年1月至2013年10月行心脏瓣膜手术后接受华法林抗凝治疗并达到华法林稳定剂量的中国汉族人群203例,对纳入人群进行CYP2C9^*3、VKORC1-1639G/A基因多态性检测,结合基因型及患者临床特征,分析对华法林稳定剂量的影响,并采用多元逐步线性回归分析建立数学模型。结果: 性别、吸烟、饮酒及高血压病史对华法林剂量无明显影响(P＞0.05)。华法林剂量与年龄呈负相关(r=-0.155,P=0.027);与身高、体质量呈正相关(r=0.166、0.190,P=0.009、0.003)。CYP2C9^*3、VKORC1-1639G/A基因多态性对华法林剂量的影响在统计学上有统计学差异(P＜0.01)。拟合得到华法林给药模型D=2.855－1.173×CYP2C9(AC)＋0.020×W－0.024×A＋4.064×VKORC1(GG)＋1.486×VKORC1(GA)。结论: 华法林的剂量受到年龄、身高、体质量及CYP2C9^*3、VKORC1-1639G/A基因多态性的影响,依据华法林给药模型可优化华法林个体化给药方案,但仍有待于临床进一步验证。

关键词: 华法林, 基因多态性, 细胞色素P4502C9, 维生素K环氧化物还原酶复合体亚单位1, 个体化给药模型

Abstract: AIM: To assess the effect of clinical factors and gene polymorphism on stable warfarin dosage in Chinese Han population,then and to establish a dose adjustment model for clinical individualized medication.METHODS: Based on the specified standard,203 patients after cardiac valve surgery and taking with stable warfarin dosage treatment in a hospital from January 2011 to October 2013 were enrolled in the study. As well,all the patients′CYP2C9^*3,VKORC1-1639G/A genetic polymorphisms were detected by PCR-RELP and sequencing technology. Effects of above-mentioned gene polymorphisms on the dose of warfarin combining with clinical characteristics of patients were analyzed and set up computation model by multiple stepwise regression analysis.RESULTS: There was no significant association between the sexgender,smoking status,drinking status and hypertension history with stable warfarin dosage (P＞0.05).The stable dose of warfarin was negatively correlated with age(r=-0.155,P=0.027) and positively correlated with body height and body weight of patients(r=0.166,0.190,P=0.009,0.003).There were statistically significance significant in the effect of CYP2C9^*3,VKORC1-1639G/A polymorphisms on the dose of warfarin (P＜0.01). A medication model D=2.855－1.173×CYP2C9(AC)＋0.020×W－0.024×A＋4.064×VKORC1(GG)＋1.486×VKORC1(GA) was obtained.CONCLUSION: It shows that age,body height,body weight and CYP2C9^*3,VKORC1-1639G/A genetic polymorphisms have influences on the stable dose of warfarin. Individualized medication of warfarin could be optimized and probably better the individualized medication of warfarin based on the model which needs to be furthermore verified in clinic.

Key words: Warfarin, gene polymorphism, cytochrome P4502C9, vitamin K epoxide reductase subunit 1, individualized dosage model

中图分类号:

R969.1

刘俊, 栾家杰, 徐文科, 朱艳虹, 汪魏平, 张大发. 中国汉族人群基于临床特征和基因型华法林个体化给药模型的研究[J]. 中国临床药理学与治疗学, 2014, 19(3): 284-290.

LIU Jun, LUAN Jia-jie, XU Wen-ke, ZHU Yan-hong, WANG Wei-ping, ZHANG Da-fa. Study on warfarin individual dosage model based on clinical factors and gene in Chinese Han population[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2014, 19(3): 284-290.

参考文献

[1] Klein TE,Altman RB,Eriksson N,et al. Estimation of the warfarin dose with clinical and pharmaeogenetic data[J].N Engl J Med,2009,360(8):753-764.
[2] Wen MS,Lee M,Chen JJ,et al. Prospective study of warfarin dosage requirements based on CYP2C9 and VKORC1 genotypes[J].Clin Pharamacol Ther,2008,84(1):83-89.
[3] Ohno M,Yamamoto A,Ono A,et al. Influence of clinical and genetic factors on warfarin dose requirements among Japanese patients[J].Eur J Clin Pharamacol,2009,65(11):1097-1103.
[4] 徐丹,刘媛,钟诗龙,等.心脏瓣膜置换术后影响华法林抗凝疗效的人口学因素分析[J].实用医学杂志,2010,26(5):750-753.
[5] 张松波,周宏灏.药物代谢性别差异及与核受体的关系[J].中国药理学通报,2007,23(3):292-294.
[6] 耿强,郭丹杰.65岁以上老年患者口服华法林抗凝的安全性探讨[J].中西医结合心脑血病杂志,2009,7(7):834-835.
[7] Hylek EM,Evans-Molina C,Shea C,et al. Major hemorrhage and tolerability of wafarin in first year of therapy among elderly patients with atrial fibrillation [J].Circulation,2007,115(21):2689-2696.
[8] Yang L,Ge W,Yu F,et al. Impact of VKORC1 gene polymorphism on inter-individual and interethnic warfarin dosage requirement-a systematic review and meta-analysis [J].Thromb Res,2010,125(4):e159-e166.
[9] Wei M,Ye F,Xie D,et al. A new algorithm to predict warfarin dose from polymorphisms of CYP4F2,CYP2C9 and VKORC1 and clinical variables:Derivation in Han Chinese patients with non valvular fibrillation[J].Thromb Haemost,2012,107(6):1083-1091.
[10] Sanderson S,Emery J,Higgins J.CYP2C9 gene variants,drug dose,and bleeding risk in warfarin-treated patients:a HuGEnet systematic review and meta-analysis[J].Genet Med,2005,7(2):97-104.
[11] Yuan HY,Chen JJ,Lee MT,et al. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity [J].Hum Mol Genet,2005,14(13):1745-1751.
[12] Reiner MJ,Reiner AP,Gage BF,et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose[J].N Engl J Med,2005,352(22):2285-2293.
[13] 张亚同,梁欣,赵楠,等.老年患者VKORC1和CYP2C9基因多态性对华法林应用的影响及分析[J].中国药学杂志,2012,47(23):1930-1933.
[14] Huang SW,Chen HS,Wang XQ,et al. Validation of VKORC1 and CYP2C9 genotypes on interindividual warfarin maintenance dose:a prospective study in Chinese patients[J].Pharmacogenet Genomics,2009,19(3):226-234.
[15] Epstein RS,Moyer TP,Aubert RE,et al.Warfarin genotyping reduces hospitalization rates results from the MM-WES(Medco-Mayo Warfarin Effectiveness study)[J].J Am Coll Cardiol,2010,55(25):2804-2812.
[16] 娄莹,谢爽,刘红,等.CYP2C9基因多态性对中国心脏机械瓣膜置换患者华法林初始抗凝效果的影响[J].中国临床药理学杂志,2013,29(1):34-41.
[17] 刘俊,徐航,葛卫红,等.华法林基于药物基因组学个体化给药方案的评价[J].中国医院药学杂志,2013,33(22):1857-1862.
[18] You JH,Wong RS,Waye MM,et al.Warfarin dosing algorithm using clinical,demographic and pharmacogenetic data from Chinese parients[J].J Thromb Thrombolysis,2011,31(1):113-118.
[19] 强亚平,汪祥海,杨浩.基因多态性与华法林个体用药的关系[J].医学综述,2012,18(1):136-139.
[20] Borgiani P,Ciccacci C,Forte V,et al.CYP4F2 genetic variant (rs2108622) significantly contributes to warfarin dosing variability in the Italian population [J].Pharmacogenomics,2009,10(2):261-266.