药物基因组学方程对上海患者华法林抗凝治疗稳定剂量预测准确性的评估

doi:10.3969/j.issn.1673-8640.2015.07.008

摘要/Abstract

摘要： 目的

在接受华法林抗凝治疗肺栓塞和心颤患者的上海患者人群中,验证华法林药物基因组学稳定剂量预测方程的准确性。

方法

收集已达华法林稳定剂量的198例患者完整的临床资料,采集每位患者枸橼酸钠抗凝1:9抗凝的外周血1.8 mL,抽提全血基因组DNA后采用高分辨率溶解曲线法检测其VKORC1-1173C>T和CYP2C9*2、CYP2C9*3基因型。采用较多使用的符合筛选条件的4个华法林稳定剂量预测模型[包括IWPC模型(基于混合种群构建)、WEN模型(基于中国台湾人群构建)、HUANG模型(基于中国大陆人群构建)及OHNO模型(基于日本人群构建)]。采用绝对误差均值(MAE)和预测百分比2个指标评价并比较各模型预测准确性。

结果

在4个预测模型中,HUANG、OHNO及WEN 3个预测模型及固定剂量方案计算的MAE<±1.0 mg/d,理想预测百分比>40%,其中MAE最低的模型为HUANG模型。理想预测百分比最高的模型为OHNO。

结论

采用亚洲人群建立的基因导向结合基本临床资料的华法林稳定剂量预测模型可以较好预测服用华法林的部分上海患者的药物剂量,具有一定临床应用价值。

关键词: 华法林, 基因型, 药物基因组学, 剂量预测模型, CYP2C9, VKORC1

Abstract: Objective

To validate the stable dose prediction accuracy of Warfarin anticoagulant therapy by pharmacogenetics among Shanghai patients with pulmonary embolism and heart fibrillation.

Methods

The complete clinical data of 198 patients with stable Warfarin dose were collected. The VKORC1-1173C>T, CYP2C9*2 and CYP2C9*3 genotypes were detected by polymerase chain reaction-high resolution melting technique after whole blood genomic DNA extraction with peripheral blood 1.8 mL of sodium citrate anticoagulation 1:9. The 4 prediction algorithms, including IWPC for mixed population, WEN for Chinese Taiwan population, HUANG for Chinese mainland population and OHNO for Japanese, were evaluated and compared by mean absolute error (MAE) and prediction accuracy.

Results

The MAE of HUANG, OHNO and WEN in 4 prediction algorithms and fixed dose model was <±1.0 mg/d with ideal prediction percentage >40%, with the minimum MAE in HUANG. The ideal prediction algorithm with highest percentage was OHNO.

Conclusions

The Warfarin stable dose algorithms by pharmacogenetics for Asian population combined with basic clinical information can predict the dose of Warfarin among Shanghai with clinical application significance.

Key words: Warfarin, Genotype, Pharmacogenetics, Dose prediction algorithm, CYP2C9, VKORC1

中图分类号:

R446.11

庄文芳, 陈燕红, 罗瑞萍, 吴婧, 宣彬彬, 曹雅楠, 杨莉, 盛慧明. 药物基因组学方程对上海患者华法林抗凝治疗稳定剂量预测准确性的评估[J]. 检验医学, 2015, 30(7): 697-702.

ZHUANG Wenfang, CHEN Yanhong, LUO Ruiping, WU Jing, XUAN Binbin, CAO Yanan, YANG Li, SHENG Huiming. Evaluation on the stable dose prediction accuracy of Warfarin anticoagulant therapy by pharmacogenetics among Shanghai patients[J]. Laboratory Medicine, 2015, 30(7): 697-702.

图/表 5

参考文献 17

[1]	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.
[2]	WADELIUS M,CHEN LY,LINDH JD,et al.The largest prospective warfarin-treated cohort supports genetic forecasting[J]. Blood, 2009,113(4): 784-792.
[3]	庄文芳,吴德沛,王兆钺. 上海地区服用华法林人群相关基因型及非遗传因素对用药剂量的影响[J].中华血液学杂志,2014,35(1):13-17.
[4]	International Warfarin Pharmacogenetics Consortium, KLEIN TE, ALTMAN RB, et al. Estimation of the warfarin dose with clinical and pharmacogenetic data[J]. N Engl J Med, 2009, 360(8): 753-764.
[5]	WEN MS,LEE M,CHEN JJ,et al.Prospective study of warfarin dosage requirements based on CYP2C9 and VKORC1 genotypes[J]. Clin Pharmacol Ther, 2008, 84(1):83-89.
[6]	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.
[7]	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 Pharmacol, 2009,65(11):1097-1103.
[8]	许俊堂,胡大一. 华法林的临床应用[J]. 中国医刊,2004,39(10):43-45.
[9]	李杰,刘双. 华法林抗凝治疗剂量的研究进展[J]. 心肺血管病杂志,2012,31(4):496-498.
[10]	祝锦,张微,张伟娟,等.中国汉族人群华法林药物基因组学剂量预测公式比较[J]. 中国药学杂志,2011,59(24):1929-1934.
[11]	谭胜蓝,彭娟,周新民,等. 验证并比较华法林稳定剂量预测模型对中国心脏瓣膜置换术后患者预测准确性[J].中国临床药理学与治疗学,2012,17(9): 1026-1033.
[12]	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.
[13]	CALDWELL MD, ANAD T, JOHNSON JA, et al.CYP4F2 genetic variant alters required warfarin dose[J]. Blood, 2008, 111(8): 4106-4112.
[14]	MCDDNALD 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.
[15]	张海燕,方焕荣,杨协清,等. 血浆蛋白C基因多态性与华法林剂量相关性的研究[J]. 中国药学杂志,2012,60(21):1741-1745.
[16]	LIU Y, YANG J, XU Q, et al.Comparative performance of warfarin pharmacogenetic algorithms in Chinese patients[J]. Thromb Res, 2012, 130(3): 435-440.
[17]	姚浩洁,赵志刚,代金玉. 影响华法令药效的药物与食物[J]. 实用心脑肺血管病杂志,2006,14(3):216.

SNP位点	引物序列(5'→3')
CYP2C9* 2(rs1799853)	正向:ATGGAAAGAAATGGAAGGAGAT
	反向:TCAACTCCTCCACAAGGC
CYP2C9* 3(rs1057910)	正向:AATAATAATATGCACGAGGTCCAGAGATGC
	反向:GATACTATGAATTTGGGACTTC
VKORC1 -1173C>T(rs9934438)	正向:GCCAGCAGGAGAGGGAAATA
	反向:AGTTTGGACTACAGGTGCCT

SNP位点	引物序列(5'→3')
CYP2C9* 2(rs1799853)	正向:ATGGAAAGAAATGGAAGGAGAT
	反向:TCAACTCCTCCACAAGGC
CYP2C9* 3(rs1057910)	正向:AATAATAATATGCACGAGGTCCAGAGATGC
	反向:GATACTATGAATTTGGGACTTC
VKORC1 -1173C>T(rs9934438)	正向:GCCAGCAGGAGAGGGAAATA
	反向:AGTTTGGACTACAGGTGCCT

模型	建模人群	目标INR	华法林平均稳定剂量(mg/d)	建模人数/ 验模人数	模型纳入因素	R²(%)
IWPC	混合种族	2.0~3.0	NA	4 043/1 009	VKORC1-1173C>T、CYP2C9*3、年龄、身高、体重、种族、肝酶诱导剂、胺碘酮	31.4
WEN	中国台湾	1.7~3.0	2.8±0.9	NA/ND	VKORC1-1173C>T、CYP2C9*3、年龄、体表面积、高血压	62.0
HUANG	中国大陆	1.8~3.0	3.0±1.2	266/156	VKORC1-1173C>T、CYP2C9*3、年龄、体表面积	54.1
OHON	日本	1.5~3.0	2.7±1.2	125/ND	VKORC1-1173C>T、CYP2C9*3、年龄、体表面积	54.8

模型	建模人群	目标INR	华法林平均稳定剂量(mg/d)	建模人数/ 验模人数	模型纳入因素	R²(%)
IWPC	混合种族	2.0~3.0	NA	4 043/1 009	VKORC1-1173C>T、CYP2C9*3、年龄、身高、体重、种族、肝酶诱导剂、胺碘酮	31.4
WEN	中国台湾	1.7~3.0	2.8±0.9	NA/ND	VKORC1-1173C>T、CYP2C9*3、年龄、体表面积、高血压	62.0
HUANG	中国大陆	1.8~3.0	3.0±1.2	266/156	VKORC1-1173C>T、CYP2C9*3、年龄、体表面积	54.1
OHON	日本	1.5~3.0	2.7±1.2	125/ND	VKORC1-1173C>T、CYP2C9*3、年龄、体表面积	54.8

VKORC1-1639 G>A	CYP2C9	起始剂量 (mg/d)
GG	1/1	5.00
GG	1/3	3.75
GG	3/3	3.75
AG	1/1	3.75
AG	1/3	2.50
AG	3/3	2.50
AA	1/1	2.50
AA	1/3	1.25
AA	3/3	1.25