华法林药物基因组学的发展及其临床应用前景

doi:10.3969/j.issn.1673-8640.2014.03.003

摘要/Abstract

摘要：

华法林是临床广泛使用的口服抗凝药物。由于自身狭窄的有效抗凝治疗范围以及个体间每日用药剂量的显著差异,困扰着许多患者和临床医生。近年来,许多研究均报道基因多态性是引起华法林个体间用药剂量差异的主要因素之一。部分学者建立基于药物基因组学的剂量方程,并在进行验证,评估其临床价值。本文综述了华法林相关药物基因组学的国内外最新进展,为进一步针对华法林的临床研究提供参考依据。

关键词: 华法林, 药物基因组学, 临床应用

Abstract:

Warfarin,a commonly prescribed anticoagulant,has warried lots of patients and doctors because of its narrow therapeutic range and large interindividual variability in daily dose. During recent years,many studies focus on genetic polymorphisms,regarding it as one of the main effects which lead to dose difference between individuals. Some of them established and verified pharmacogenetic-based warfarin-dosing algorithms and evaluated the clinical significance. Our review exhibits the latest development of warfarin-related pharmacogenomics home and abroad,in order to provide references for further clinical studies.

Key words: Warfarin, Pharmacogenomics, Clinical application

中图分类号:

Q503

吴炯，邬升超综述，郭玮，潘柏申审校. 华法林药物基因组学的发展及其临床应用前景[J]. 检验医学, 2014, 29(3): 209-214.

WU Jiong, WU Shengchao, GUO Wei, PAN Baishen.. Development of warfarin-related pharmacogenomics and its prospect of clinical application[J]. , 2014, 29(3): 209-214.

参考文献

[1] Hirsh J,Fuster V,Ansell J,et al. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy[J].J Am Coll Cardiol,2003,41(9):1633-1652.
[2] Redman AR. Implications of cytochrome P450 2C9 polymorphism on warfarin metabolism and dosing[J].Pharmacotherapy,2001,21(2):235-242.
[3] Lindh JD,Holm L,Andersson ML,et al. Influence of CYP2C9 genotype on warfarin dose requirements-a systematic review and meta-analysis[J].Eur J Clin Pharmacol,2009,65(4):365-375.
[4] 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.
[5] Miao L,Yang J,Huang C,et al. Contribution of age,body weight,and CYP2C9 and VKORC1 genotype to the anticoagulant response to warfarin: proposal for a new dosing regimen in Chinese patients[J].Eur J Clin Pharmacol,2007,63(12):1135-1141.
[6] Voora D,Eby C,Linder MW,et al. Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype[J].Thromb Haemost,2005,93(4):700-705.
[7] Yang L,Ge W,Yu F,et al. Impact of VKORC1 gene polymorphism on interindividual and interethnic warfarin dosage requirement-a systematic review and meta analysis[J].Thromb Res,2010,125(4):e159-e166.
[8] Jiang NX,Song J,Xu B. Vitamin K epoxide reductase complex 1 gene polymorphism and warfarin dose requirement in Chinese patients[J].Zhonghua Xin Xue Guan Bing Za Zhi,2007,35(7):652-654.
[9] Lund K,Gaffney D,Spooner R,et al. Polymorphisms in VKORC1 have more impact than CYP2C9 polymorphisms on early warfarin International Normalized Ratio control and bleeding rates[J].Br J Haematol,2012,158(2):256-261.
[10] McDonald MG,Rieder MJ,Nakano M,et al. CYP4F2 is a vitamin K1 oxidase: an explanation for altered warfarin dose in carriers of the V433M variant[J]. Mol Pharmacol,2009,75(6):1337-1346.
[11] Cen HJ,Zeng WT,Leng XY,et al. CYP4F2 rs2108622: a minor significant genetic factor of warfarin dose in Han Chinese patients with mechanical heart valve replacement[J].Br J Clin Pharmacol,2010,70(2):234-240.
[12] Danese E,Montagnana M,Johnson JA,et al. Impact of the CYP4F2 p.V433M polymorphism on coumarin dose requirement: systematic review and meta-analysis[J].Clin Pharmacol Ther,2012,92(6):746-756.
[13] Huang SW,Xiang DK,Huang L,et al. Influence of GGCX genotype on warfarin dose requirements in Chinese patients[J].Thromb Res,2011,127(2):131-134.
[14] Wadelius M,Chen LY,Eriksson N,et al. Association of warfarin dose with genes involved in its action and metabolism[J]. Hum Genet,2007,121(1):23-34.
[15] Gu Q,Kong Y,Schneede J,et al. VKORC1-1639G> A,CYP2C9,EPHX1691A> G genotype,body weight,and age are important predictors for warfarin maintenance doses in patients with mechanical heart valve prostheses in southwest China[J].Eur J Clin Pharmacol,2010,66(12):1217-1227.
[16] Wang TL,Li HL,Tjong WY,et al. Genetic factors contribute to patient-specific warfarin dose for Han Chinese[J].Clin Chim Acta,2008,396(1):76-79.
[17] Zhang W,Zhang WJ,Zhu J,et al. Genetic polymorphisms are associated with variations in warfarin maintenance dose in Han Chinese patients with venous thromboembolism[J].Pharmacogenomics,2012,13(3):309-321.
[18] Lee MT,Chen CH,Chou CH,et al. Genetic determinants of warfarin dosing in the Han-Chinese population[J].Pharmacogenomics,2009,10(12):1905-1913.
[19] Zhong SL,Yu XY,Liu Y,et al. Integrating interacting drugs and genetic variations to improve the predictability of warfarin maintenance dose in Chinese patients[J].Pharmacogenet Genomics,2012,22(3):176-182.
[20] 吴薇,李艳,童永清,等. DNA 测序法检测华法林用药剂量相关基因多态性的应用价值[J].中华检验医学杂志,2012,35(11):1016-1020.
[21] Liang R,Li L,Li C,et al. Impact of CYP2C9^* 3,VKORC1-1639,CYP4F2rs2108622 genetic polymorphism and clinical factors on warfarin maintenance dose in Han-Chinese patients[J].J Thromb Thrombolysis,2012,34(1):120-125.
[22] 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 atrial fibrillation[J].Thromb Haemost,2012,107(6):1083-1091.
[23] Huang SW,Xiang DK,Wu HL,et al. Impact of five genetic polymorphisms on inter-individual variation in warfarin maintenance dose[J].Zhonghua Yi Xue Yi Chuan Xue Za Zhi,2011,28(6):661-665.
[24] 罗万慰,张海燕,马守梅,等. 环氧化物水解酶 1 基因多态性对华法林剂量影响的研究[J].中国药学杂志,2010,45(19):1488-1491.
[25] Wadelius M,Chen LY,Eriksson N,et al. Association of warfarin dose with genes involved in its action and metabolism[J].Hum Genet,2007,121(1):23-34.
[26] 崔广林,丁虎,徐宇军,等. 高分辨率熔解曲线方法在指导华法林使用起始剂量基因分型中的应用及临床各种基因分型方法的比较[J].中华心血管病杂志,2012,40(6):477-481.
[27] Zhu J,Zhang W,Li Y,et al. ARMS test for diagnosis of CYP2C9 and VKORC1 mutation in patients with pulmonary embolism in Han Chinese[J].Pharmacogenomics,2010,11(1):113-119.
[28] Sconce EA,Khan TI,Wynne HA,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(7):2329-2333.
[29] Gong IY,Tirona RG,Schwarz UI,et al. Prospective evaluation of a pharmacogenetics-guided warfarin loading and maintenance dose regimen for initiation of therapy[J].Blood,2011,118(11):3163-3171.
[30] Wang M,Lang X,Cui S,et al. Clinical application of pharmacogenetic-based warfarin-dosing algorithm in patients of Han nationality after rheumatic valve replacement: a randomized and controlled trial[J].Int J Med Sci,2012,9(6):472-479.
[31] Wadelius M. Point: use of pharmacogenetics in guiding treatment with warfarin[J].Clin Chem,2009,55(4):709-711.
[32] McWilliam A,Lutter R,Nardinelli C. Healthcare impact of personalized medicine using genetic testing: an exploratory analysis for warfarin[J].Personalized Medicine,2008,5(3):279-284.
[33] Wu AH. Use of genetic and nongenetic factors in warfarin dosing algorithms[J].Pharmacogenomics,2007,8(7):851-861.
[34] 庄文芳,吴婧,李莉.华法林给药剂量预测模型的建立与应用[J]. 检验医学,2013,28(12):1157-1161.