华法林的基因组学研究进展

摘要/Abstract

摘要： 华法林是临床上广泛使用的香豆素类口服抗凝血药, 其狭窄的抗凝治疗指数范围和抗凝不当所致的并发症一直困扰着临床医生, 如何合理使用已经成为一个难题。近年来随着分子生物学的快速发展, 研究发现药动学和药效学多个相关基因的多态性造成了个体差异, 影响了华法林的使用剂量。本文综述了药物基因组学研究在华法林使用中的国内外最新进展, 为华法林个体化使用提供参考依据。

关键词: 华法林, 药物基因组学, 基因多态性

Abstract: Warfarin is widely used as one of the coumarins anticoagulation drugs in the clinical.Every physician has been disturbed by its narrow therapic index and bleeding complications.It is a difficult thing for the doctor to use it rationally.However, recently, with the rapid development of molecule biology, some research find that gene polymorphism of pharmacodynamics and pharmacokinetics cause the individual variability in drug response.In this review,we focus on the latest development in pharmacogenomics of warfarin at home and abroad in order to give some suggestions for the individual use of warfarin.

Key words: warfarin, pharmacogenomics, gene polymorphism

中图分类号:

R969
R966

杨剑, 缪丽燕. 华法林的基因组学研究进展[J]. 中国临床药理学与治疗学, 2006, 11(12): 1326-1331.

YANG Jian, MIAO Li-yan. Research advances in pharmacogenomics of warfarin[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2006, 11(12): 1326-1331.

参考文献

1 许俊堂, 胡大一.华法林的临床应用[J].中国医刊, 2004;39:43-6
2 陈晓晖, 赵树进, 袁进.CYP2C9 基因多态性与药物代谢及疾病关系研究进展[J].药物流行病学杂志, 2005;14:178-80
3 Kamali F, Khan TI, King BP, Frearson R, Kesteven P,Wood P,et al.Contribution of age, body size, and CYP2C9 genotype to anticoagulant response to warfarin[J].Clin Pharmacol Ther,2004;75:204-12
4Siguret V, Gouin I, Golmard JL, Geoffroy S, Andreux JP, Pautas E.Cytochrome P450 2C9 polymorphisms (CYP2C9) and warfarin maintenance dose in elderly patients[J].Revue de Medecine Interne, 2004;25:271-4
5Aithal GP, Day CP, Kesteven PJL, Daly AK.Association of polymorphisms in the cytochrome P450 CYP2C9 with dose requirement and risk of bleeding complications[J].Lancet, 1999;353:717-9
6 Sanderson S, Emery J, Higgins J.CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients:A HuGEnet(tm) systematic review and meta-analysis[J].GenetMed, 2005;7:98-104
7 Margaglione M, Colaizzo D, D' Andrea G, Brancaccio V, Ciampa A,Grandone E.Genetic modulation of oral anticoagulation with warfarin[J].Thromb Haemost, 2000;84:775-8
8 HigashiMK, Veenstra DL, Kondo LM,Wittkowsky AK, Srinouanprachanh SL, Farin FM, et al.Association between CYP2C9 genetic variations anticoagulation-related outcomes during warfarin therapy[J].JAMA, 2002;287:1691-8
9 Hermida J, Zarza J, Alberca I, Montes R, Lopez ML, Molina E,et al.Differential effects of 2C9＊3 and 2C9＊2 variants of cytochrome P450 CYP2C9 on sensitivity to acenocoumarol [J].Blood, 2002;99:4237-9
10 Taube J, Halsall D, Baglin T.Influence of cytochrome P450 CYP2C9 polymorphisms on warfarin sensitivity and risk of overanticoagulation in patients on long-term treatment[J].Blood,2000;96:1816-9
11 HillmanMA,Wilke RA, CaldwellMD, Berg RL, Glurich I, Burmester JK.Relative impact of covariates in prescribing warfarin according to CYP2C9 genotype[J].Pharmacogenetics, 2004;14:539-47
12 Linder MW, Looney S, Adams JE, Johnson N, Antonino-Green D, Lacefield N, et al.Warfarin Dose Adjustments Based on CYP2C9 Genetic Polymorphisms[J].J Thromb Thrombolysis,2002;14:227-32
13 Joffe HV, Xu R, Johnson FB, Longtine J, Kucher N, Goldhaber SZ.Warfarin dosing and cytochrome P450 2C9 polymorphisms[J].Thromb Haemost, 2004;91:1123-8
14 Zhao F, Loke C, Rankin SC, Guo JY, Lee HS, Wu TS, et al.Novel CYP2C9 genetic variants in Asian subjects and their influence on maintenance warfarin dose[J].Clin Pharmacol Ther,2004;76:210-9
15 马量, 余国伟, 叶丁生, 徐鹤云, 邬志勇, 姚航平.细胞色素P4502C9-Leu359 基因变异与华法林抗凝治疗研究[J].心脑血管病防治, 2001;1:21-3
16 李奇林, 谷天祥.CYP2C9 基因的多态性对30 名汉族心脏病患者华法林稳定维持量的影响[D].沈阳:中国医科大学, 2004
17 Leung AY, Chow HC, Kwong YL, Lie AK, Fung AT, Chow WH, et al.Genetic polymorphism in exon 4 of cytochrome P450 CYP2C9 may be associated with warfarin sensitivity in Chinese patients[J].Blood, 2001;98:2584-7
18 Freeman BD, Zehnbauer BA, McGrath S, Borecki I, Buchman TG.Cytochrome P450 polymorphisms are associated with reduced warfarin dose[J].Surgery, 2000;128:281-5
19 WadeliusM, Sorlin K,Wallerman O, Karlsson J, Yue QY, Magnusson PK, et al.Warfarin sensitivity related to CYP2C9,CYP3A5, ABCB1 (MDR1) and other factors[J].Pharmacogenomics J, 2004;4:40-8
20 Kragh-Hansen U, Brennan SO, Galliano M, Sugita O.Binding of warfarin, salicylate, and diazepam to genetic variants of human serum albumin with known mutations[J].Mol Pharmacol, 1990;37:238-42
21 Vestberg K, Galliano M, Minchiotti L, Kragh-Hansen U.Highaffinity binding of warfarin, salicylate and diazepam to natural mutants of human serum albumin modified in the C-terminal end[J].Biochem Pharma, 1992;44:1515-21
22 Watanabe H, Kragh-Hansen U, Tanase S, Nakajou K, Mitarai M, Iwao Y, et al.Conformational stability and warfarin-binding properties of human serum albumin studied by recombinant mutants[J].Biochem J, 2001;357;269-74
23 周宏灏.遗传药理学[M].第1 版.北京:科学出版社,2001:269-70
24 Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hortnagel K,Pelz HJ, et al.Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2[J].Nature,2004;427;537-41
25 Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW.Identification of the gene for vitamin K epoxide reductase[J].Nature, 2004;427:541-4
26 Sconce EA, Khan TI,Wynne HA, Avery P, Monkhouse L, King BP, et al.The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements:proposal for a new dosing regimen[J].Blood, 2005;106:2329-33
27 Obayashi K, Nakamura K, Kawana J, Ogata H, Hanada K,Kurabayashi M.VKORC1 gene variations are the major contributors of variation in warfarin dose in Japanese patients[J].Clin Pharmacol Ther, 2006;80:169-78
28 Wadelius M, Chen LY, Downes K, Ghori J, Hunt S, Eriksson N,et al.Common VKORC1 and GGCX polymorphisms associated with warfarin dose[J].Pharmacogenomics J, 2005;5:262-70
29 D' Andrea G, D' Ambrosio RL, Di Perna P, Chetta M, Santacroce R, Brancaccio V, et al.A polymorphism in the VKORC1 gene is associated with an interindividual variability in the doseanticoagulant effect of warfarin[J].Blood, 2005;105:645-9
30 Bodin L, Verstuyft C, Tregouet DA, Robert A, Dubert L, Funck-Brentano C, et al.Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity[J].Blood, 2005;106:135-40
31 Yuan HY, Chen JJ, LeeMT,Wung JC, Chen YF, Charng MJ, 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;14:1745-51
32 Veenstra DL, You JH, Rieder MJ, Farin FM, Wilkerson HW,Blough DK, et al.Association of Vitamin K epoxide reductase complex 1 (VKORC1) variants with warfarin dose in a Hong Kong Chinese patient population[J].Pharmacogenet Genomics,2005;15:687-91
33 Geisen C,Watzka M, Sittinger K, SteffensM, Daugela L, Seifried E, et al.VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation[J].Thromb Haemost, 2005;94:773-9
34 Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS,McLeod H, et al.Effect of VKORC1 Haplotypes on Transcriptional Regulation and Warfarin Dose[J].N Engl J Med, 2005;352:2285-93
35 Lee SC, Ng SS, Oldenburg J, Chong PY, Rost S, Guo JY, et al.Interethnic variability of warfarin maintenance requirement is explained by VKORC1 genotype in an Asian population[J].Clin Pharmacol Ther, 2006;79:197-205
36 Montes R, Ruiz de Gaona E, Martinez-Gonzalez MA, Alberca I,Hermida J.The c.-1639G >A polymorphism of the VKORC1 gene is a major determinant of the response to acenocoumarol in anticoagulated patients[J].Br J Haematol, 2006;133:183-7
37 SchalekamPT, Brasse BP, Roijers JF, Chahid Y, van Geest-DaalderoPJH, de Vries-Goldschmeding H, et al.VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status:interaction between both genotypes affects overanticoagulation[J].Clin Pharmacol Ther, 2006;80:13-22 Chin J Clin Pharmacol Ther 2006 Dec;11(12)
38 Reitsma PH, van der Heijden JF, Groot AP, Rosendaal FR,Buller HR.A C1173T dimorphism in the VKORC1 gene determines coumarin sensitivity and bleeding risk[J].PLoS Med,2005;2:e312
39 Takahashi H, Wilkinson GR, Nutescu EA, Morita T, Ritchie MD, Scordo MG, et al.Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra-and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans[J].Pharmacogenet Genomics, 2006;16:101-10
40 Aquilante CL, Langaee TY, Lopez LM, Yarandi HN, Tromberg JS,MOhuczy D, et al.Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements[J].Clin Pharmacol Ther, 2006;79:291-302
41 Loebstein R, Vecsler M, Kurnik D, Austerweil N, Gak E, Halkin H, et al.Common genetic variants of microsomal epoxide hydrolase affect warfarin dose requirements beyond the effect of cytochrome P450 2C9[J].Clin Pharmacol Ther, 2005;77:365-72
42 Rost S, Fregin A, Koch D, CompesM, Muller CR, Oldenburg J.Compound heterozygous mutations in the gamma-glutamyl carboxylase gene cause combined deficiency of all vitamin K-dependent blood coagulation factors[J].Br J Haematol, 2004;126:546-9
43 Kohnke H, Sorlin K,Granath G,WadeliusM.Warfarin dose related to apolipoprotein E (APOE ) genotype[J].Clin Pharmacol J, 2005;61:381-8
44 Kohnke H, Scordo MG, Pengo V, Padrini R,WadeliusM.Apolipoprotein E (APOE) and warfarin dosing in an Italian population[J].Clin Pharmacol J, 2005;61:781-3

[1]	李坤, 李璐璐, 李楠楠, 胡卫红, 周建超. 成人肾移植术后血糖控制和CYP3A5基因多态性对他克莫司谷浓度的影响[J]. 中国临床药理学与治疗学, 2023, 28(7): 767-774.
[2]	李青华, 赵艳, 赵海港, 高朋飞, 徐炳欣. ABCB1 G2677T 基因多态性检测在缺血性脑卒中患者应用阿托伐他汀降脂治疗中的价值[J]. 中国临床药理学与治疗学, 2023, 28(6): 633-640.
[3]	朱丽, 魏兵, 廖世峨, 张超, 郑晓宇, 刘亚军. 药物代谢酶细胞色素P450单核苷酸多态性影响哮喘儿童吸入皮质醇激素疗效研究[J]. 中国临床药理学与治疗学, 2023, 28(5): 536-543.
[4]	刘秀梅, 郭倩倩, 方圆, 陈楠, 齐琦. 经颈静脉肝内门体分流术后患者抗栓治疗的药学监护实践[J]. 中国临床药理学与治疗学, 2023, 28(5): 556-560.
[5]	张志英, 靳秀红, 张小宁, 张向峰, 罗青林, 张松林. TBX21和ADCY9多态性在儿童哮喘发生发展中的临床研究[J]. 中国临床药理学与治疗学, 2023, 28(4): 407-412.
[6]	刘璐, 石雨菲, 何庆烽, 徐凤艳, 王鲲, 蔡卫民, 相小强. 群体模型分析方法评估基因多态性对药物PK/PD的影响[J]. 中国临床药理学与治疗学, 2023, 28(11): 1275-1282.
[7]	王爽, 刘嘉, 张月丽. POR*28基因多态性与中国肾移植患者他克莫司稳定剂量的相关性研究[J]. 中国临床药理学与治疗学, 2022, 27(9): 991-997.
[8]	付虹, 田磊. 缺血性脑卒中伴高血压病患者个体化精准治疗的研究[J]. 中国临床药理学与治疗学, 2022, 27(8): 870-876.
[9]	陈文刚, 殷勤, 张巍巍, 周露露, 寇婉青, 袁小龙. 皖南地区高血压患者MTHFR基因多态性分布及与血Hcy相关性研究[J]. 中国临床药理学与治疗学, 2022, 27(7): 768-774.
[10]	武元竹, 刘俊, 杨魁, 彭静, 栾家杰, 韦俊, 张大发, 宋帅, 袁小龙, 王中方, 张年宝, 解丹, 姜鹏, 范洁. 安徽地区汉族人群CYP2C9*3和VKORC1-1639G>A基因多态性分布及对华法林稳定剂量的影响[J]. 中国临床药理学与治疗学, 2022, 27(6): 652-659.
[11]	连金芳, 刘亦伟, 林翠鸿, 黄品芳, 林荣芳. 华法林PPK/PD模型与多元回归法剂量模型的预测准确度比较[J]. 中国临床药理学与治疗学, 2022, 27(3): 267-273.
[12]	孙媛媛, 邓锟红, 王思懿, 况赟, 邹婵, 郭成贤, 何庆南, 刘和林, 阳国平. 个体化用药基因电子身份应用程序的设计与实现[J]. 中国临床药理学与治疗学, 2022, 27(3): 274-280.
[13]	陈佳音, 王丽, 王立军, 童刚领, 马洁, 陈西敬, 卢杨. 有机阳离子转运体基因多态性与奥沙利铂毒性及疗效的相关性研究[J]. 中国临床药理学与治疗学, 2022, 27(2): 171-177.
[14]	张进华, 刘茂柏, 蔡铭智, 郑英丽, 劳海燕, 向倩, 都丽萍, 朱珠, 董婧, 左笑丛, 李新刚, 尚德为, 陈冰, 叶岩荣, 王玉珠, 高建军, 张健, 陈万生, 谢海棠, 焦正. 模型引导的华法林精准用药：中国专家共识（2022版）[J]. 中国临床药理学与治疗学, 2022, 27(11): 1201-1212.
[15]	温都苏, 王毅, 孙建军. 贝叶斯法与多元线性回归法预测华法林剂量模型的比较研究[J]. 中国临床药理学与治疗学, 2022, 27(1): 33-38.