中国人群中抗结核药物引发肝损伤的易感基因标记研究

doi:10.16288/j.yczz.19-271

遗传 ›› 2020, Vol. 42 ›› Issue (4): 374-379.doi: 10.16288/j.yczz.19-271

中国人群中抗结核药物引发肝损伤的易感基因标记研究

周晨希, 李沫, 怀聪, 贺林, 秦胜营()

上海交通大学Bio-X研究院,上海 200030

收稿日期:2019-11-24 修回日期:2019-12-26 出版日期:2020-04-20 发布日期:2020-02-26
通讯作者: 秦胜营 E-mail:chinsir@sjtu.edu.cn
作者简介:周晨希,硕士,专业方向：生物学。E-mail: chenxizhou@sjtu.edu.cn
基金资助:
国家自然科学基金项目编号(81773818);国家自然科学基金项目编号(81273596);国家自然科学基金项目编号(30900799);国家自然科学基金项目编号(81671326);上海市浦江人才计划项目资助编号(17PJD020)

Study on hereditary susceptibility genetic markers to anti-tuberculosis drug induced liver injury in Chinese population

Chenxi Zhou, Mo Li, Cong Huai, Lin He, Shengying Qin()

Bio-X Institute, Shanghai Jiaotong University, Shanghai 200030, China

Received:2019-11-24 Revised:2019-12-26 Online:2020-04-20 Published:2020-02-26
Contact: Qin Shengying E-mail:chinsir@sjtu.edu.cn
Supported by:
Supported by the National Natural Science Foundation of China Nos(81773818);Supported by the National Natural Science Foundation of China Nos(81273596);Supported by the National Natural Science Foundation of China Nos(30900799);Supported by the National Natural Science Foundation of China Nos(81671326);Shanghai Pujiang Program No(17PJD020)

摘要/Abstract

摘要：

为系统性研究中国人群中抗结核药物引发肝损伤的易感基因标记,本研究以41例抗结核药物引发肝损伤的病人和39例健康对照为研究对象,采用Haloplex捕获测序的方法对其基因组中药物代谢、转运和免疫相关通路的109个基因进行靶向测序。用Plink软件对DNA突变位点与肝损伤的发生进行关联分析,以千人基因组计划东亚人群作为对照组,对显著性位点进行验证,并用SIFT和Polyphen2软件对预测显著关联的位点进行功能预测。结果发现UGT1A4 rs2011404 (χ ² = 4.6809, P =0.0305)是抗结核药物引发的肝损伤的易感基因标记,且rs2011404突变可能引起UGT1A4蛋白的功能障碍。本研究为临床上对抗结核药物的合理用药提供了有益的参考。

关键词: 抗结核药物, 肝损伤, 关联分析, UGT1A4

Abstract:

To systematically study the susceptible genetic markers for liver injury induced by anti-tuberculosis drugs in the Chinese population, 109 genes related to drug metabolism, transport and immunity were captured by Haloplex capture technique from DNA samples of 41 patients with liver injury induced by anti-tuberculosis drugs and 39 healthy controls, and sequenced completely. Association study was conducted using Plink software. To verify the significant candidate SNPs, the χ ² study was expanded to the control group from the 1000-person Genome Project of the East Asian population. SIFT and Polyphen2 software were used to predict the functional significance of the associated SNPs. Our results identified the UGT1A4 rs2011404 (χ ² = 4.6809, P = 0.0305) as a susceptible genetic marker for liver injury induced by anti-tuberculosis drugs, and rs2011404 mutation might contribute to UGT1A4 protein dysfunction. This study has provided a potentially useful reference for establishing the precision medicine in rational uses of anti-tuberculosis drugs in the clinic.

Key words: anti-tuberculosis drug, liver injury, association study, UGT1A4

周晨希, 李沫, 怀聪, 贺林, 秦胜营. 中国人群中抗结核药物引发肝损伤的易感基因标记研究[J]. 遗传, 2020, 42(4): 374-379.

Chenxi Zhou, Mo Li, Cong Huai, Lin He, Shengying Qin. Study on hereditary susceptibility genetic markers to anti-tuberculosis drug induced liver injury in Chinese population[J]. Hereditas(Beijing), 2020, 42(4): 374-379.

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基因类型	基因家族	目标捕获基因
一相药物代谢基因	CYP家族基因	CYP1A1、CYP1A2、CYP1B1、CYP2A13、CYP2A6、CYP2A7、CYP2B6、CYP2C18、CYP2C19 CYP2C8、CYP2C9、CYP2D6、CYP2E1、CYP2F1、CYP2J2、CYP2R1、CYP2S1、CYP2U1、 CYP2W1、CYP3A4、CYP3A43、CYP3A5、CYP3A、CYP4V2、CYP4X1和CYP4Z1
	超氧化物歧化酶	SOD1、SOD2和SOD3
	含黄素单加氧化酶	FMO1、FMO2、FMO3、FMO4和FMO5
	其他	TPMT
二相药物代谢基因	UGT家族	UGT1A1、UGT1A3、UGT1A4、UGT1A6、UGT1A9、UGT2B15和UGT2B7
	GST家族	GSTM1和GSTT1
	NAT家族	NAT1和NAT2
三相药物转运蛋白	ATP结合盒式转运蛋白	ABCB1、ABCB11、ABCB4、ABCC1、ABCC10、ABCC1、ABCC12、ABCC2、ABCC3、ABCC4、ABCC5和ABCC6
三相药物转运蛋白	其他转运蛋白	SLCO1B1、POU2F1和POU5F1
调控受体	调控受体	AHR、ARNT、ESR1、ESR2、FOXA1、FOXA2、FOXA3、HNF1A、HNF1B、HNF4A、HNF4G、NR1H2、NR1H3、NR1H4、NR1I、NR1I3、PPARA、PPARD、PPARG、RARA、RARB、RARG和VDR
固有免疫	白细胞介素	IL10、IL12A、IL12B、IL13、IL18、IL1A、IL1B、IL2、IL4、IL5、IL6、IL7和IL9
固有免疫	其他细胞激素	CCL2、IFNG和TNF
适应性免疫	人类白细胞抗原	HLA-A、HLA-B、HLA-C、HLA-DPA1、HLA-DPB1、HLA-DQA1、HLA-DQB1、HLA-DRA和HLA-DRB1

基因	编号	频数 REF/ALT		比值比(OR)	95%置信区间(95%CI)	P值
基因	编号	结核病人	健康人	比值比(OR)	95%置信区间(95%CI)	P值
UGT1A4	rs2011404	6/74	23/55	0.1939	0.0740~0.5083	0.0004
CYP2D6	rs16947	64/12	70/2	6.5620	1.4140~30.4500	0.0069
CYP2S1	rs338599	71/9	56/18	0.3944	0.1646~0.9446	0.0330

基因	编号	等位基因 REF/ALT	等位基因频率		卡方(χ²)	P值
基因	编号	等位基因 REF/ALT	结核病人	东亚健康人群数据库	卡方(χ²)	P值
UGT1A4	rs2011404	T/G	0.0750/0.9250	0.0258/0.9742	4.6809	0.0305
CYP2D6	rs16947	G/A	0.8421/0.1579	0.8601/0.1399	0.0698	0.7917
CYP2S1	rs338599	C/G	0.8875/0.1125	0.7897/0.2103	3.7978	0.0513

基因	编号	位置	等位基因	氨基酸改变	SIFT预测	PolyPhen2预测
UGT1A4	rs2011404	编码区	T>G	C157W或C157C	deleterious	Probably damaging
CYP2D6	rs16947	编码区	G>A	R296C或R274C或R245C	tolerated	Benign
CYP2S1	rs338599	编码区	C>G	P74P	tolerated	-

中国人群中抗结核药物引发肝损伤的易感基因标记研究

Study on hereditary susceptibility genetic markers to anti-tuberculosis drug induced liver injury in Chinese population

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