广西壮族自治区结核分枝杆菌异烟肼与利福平耐药基因联合突变特征分析

秦翊翔 蓝如束 覃慧芳 叶婧 秦小玲 甘丽 刘港 徐若兰 罗丹

秦翊翔, 蓝如束, 覃慧芳, 叶婧, 秦小玲, 甘丽, 刘港, 徐若兰, 罗丹. 广西壮族自治区结核分枝杆菌异烟肼与利福平耐药基因联合突变特征分析[J]. 疾病监测, 2022, 37(6): 787-791. doi: 10.3784/jbjc.202112120636
引用本文: 秦翊翔, 蓝如束, 覃慧芳, 叶婧, 秦小玲, 甘丽, 刘港, 徐若兰, 罗丹. 广西壮族自治区结核分枝杆菌异烟肼与利福平耐药基因联合突变特征分析[J]. 疾病监测, 2022, 37(6): 787-791. doi: 10.3784/jbjc.202112120636
Qin Yixiang, Lan Rushu, Qin Huifang, Ye Jing, Qin Xiaoling, Gan Li, Liu Gang, Xu Ruolan, Luo Dan. Characterization of combined mutation of isoniazid and rifampicin resistance genes in Mycobacterium tuberculosis in Guangxi[J]. Disease Surveillance, 2022, 37(6): 787-791. doi: 10.3784/jbjc.202112120636
Citation: Qin Yixiang, Lan Rushu, Qin Huifang, Ye Jing, Qin Xiaoling, Gan Li, Liu Gang, Xu Ruolan, Luo Dan. Characterization of combined mutation of isoniazid and rifampicin resistance genes in Mycobacterium tuberculosis in Guangxi[J]. Disease Surveillance, 2022, 37(6): 787-791. doi: 10.3784/jbjc.202112120636

广西壮族自治区结核分枝杆菌异烟肼与利福平耐药基因联合突变特征分析

doi: 10.3784/jbjc.202112120636
基金项目: 广西自然科学基金面上项目(No. 2017GXNSFAA198330);广西中医药大学博士科研启动项目(No. 2017BS004);广西中医药大学研究生创新项目(No. YCSW2021226);广西医疗卫生适宜技术开发与推广应用项目(No. S2017066)
详细信息
    作者简介:

    秦翊翔,男,广西壮族自治区桂林市人,研究生在读,主要从事结核病流行病学,Email:794248760@qq.com

    通讯作者:

    罗丹,Tel:0771–4928360,Email:Luodan.2005@163.com

  • 中图分类号: R211; R521

Characterization of combined mutation of isoniazid and rifampicin resistance genes in Mycobacterium tuberculosis in Guangxi

Funds: This study was supported by the Natural Science Foundation of Guangxi (No. 2017GXNSFAA198330), the Doctoral Research Initiation Program of Guangxi University of Traditional Chinese Medicine (No. 2017BS004), the Graduate Student Innovation Program of Guangxi University of Traditional Chinese Medicine (No. YCSW2021226) and Guangxi Medical Health Suitable Technology Development, Promotion and Application Project (No. S2017066)
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  • 摘要:   目的   了解广西壮族自治区(广西)结核分枝杆菌异烟肼与利福平耐药基因联合突变特征,为耐多药结核病的分子诊断和治疗提供依据。  方法   2017—2018年从广西30个结核病防治定点机构收集的结核分枝杆菌中选取49株耐多药菌株和459株全敏感菌株进行全基因组测序。  结果   耐多药表型与基因联合突变的符合率为71.43%。 单基因突变率和基因联合突变率在耐多药菌株中均高于全敏感菌株(χ2=5.753,P=0.016; χ2=284.034,P<0.001)。 katGrpoB的单基因突变率在耐多药菌株中高于全敏感菌株(χ2=7.524,P=0.006; χ2=4.353,P=0.037)。 katGrpoB基因联合突变在耐多药菌株中高于全敏感菌株(χ2=279.956,P<0.001)。 在基因联合突变的位点分布中,以katG315+rpoB450和katG315+rpoB445位点突变为主,占40.82%(20/49),2种形式的基因位点联合突变率在耐多药菌株中均高于全敏感菌株(χ2=144.232,P<0.001; χ2=19.014,P<0.001)。  结论   对异烟肼和利福平耐药基因联合突变的检测可作为广西耐多药筛查的重要指标。 广西结核分枝杆菌异烟肼和利福平耐药基因突变以katG315、rpoB450和rpoB445位点突变为主,基因联合突变以katGrpoB形式为主。 katG315+rpoB450和katG315+rpoB445位点突变是广西地区耐多药产生的主要分子机制。
  • 表  1  基因测序结果与比例法药敏结果的比较

    Table  1.   Comparison of gene sequencing results with drug susceptibility results by ratio method

    基因测序比例法药敏(株)总计
    (株)
    耐多药全敏感
    INH+RFP基因联合突变35 6 41
    未发生联合突变14453467
    合计49459508
    注:INH. 异烟肼;RFP. 利福平
    下载: 导出CSV

    表  2  耐多药和全敏感菌株中异烟肼与利福平耐药基因突变分布情况

    Table  2.   Distribution of mutations between isoniazid and rifampicin resistance genes in MDR and fully sensitive strains

     基因耐多药
    n=49)
    全敏感
    n=459)
    χ2P
    突变(株)突变率(%)突变(株)突变率(%)
    单基因突变714.29224.795.7530.016a
     katG48.1661.317.5240.006a
     kasA00.0030.650.0001.000a
     fabG100.0081.740.1080.743a
     rpoB36.1251.094.3530.037a
    基因联合突变3571.4361.31284.034<0.001a
      katGrpoB3367.3540.87279.956<0.001a
      inhArpoB12.0400.001.8720.171a
      ahpCrpoB12.0410.000.5430.461a
      kasArpoB00.0010.221.000b
    注:a. 矫正χ2值,b. Fisher精确概率,−. 无数据
    下载: 导出CSV

    表  3  异烟肼与利福平耐药基因联合突变位点分布

    Table  3.   Distribution of combined mutation sites of isoniazid and rifampicin resistance genes

     基因位点突变碱基氨基酸耐多药(n=49)全敏感
    n=459)
    χ2P
    菌株数(株)突变率
    (%)
    菌株数(株)突变率(%)
    katGrpoB315+450AGC-ACC+TCG-TTG丝氨酸-苏氨酸+丝氨酸-亮氨酸1632.6500.00144.2320.000a
    katGrpoB315+445AGC-ACC+CAC-TAC丝氨酸-苏氨酸+组氨酸-酪氨酸 48.1600.00 19.0140.000a
    katGrpoB315+450AGC-AAC+TCG-TTG丝氨酸-天冬酰胺+丝氨酸-亮氨酸 12.0400.000.171b
    katGrpoB315+452AGC-ACC+CTG-CCG丝氨酸-苏氨酸+亮氨酸-脯氨酸 12.0400.000.171b
    katGrpoB315+445AGC-ACC+CAC-AAC丝氨酸-苏氨酸+组氨酸-天冬酰胺 12.0400.000.171b
    katGrpoB315+445AGC-ACC+CAC-CCC丝氨酸-苏氨酸+组氨酸-脯氨酸 12.0400.000.171b
    katGrpoB315+445AGC-AAC+CAC-GAC丝氨酸-苏氨酸+组氨酸-天冬氨酸 12.0400.000.171b
    katGrpoB315+435AGC-AAC+CAC-CTC丝氨酸-天冬酰胺+天冬氨酸-缬氨酸 12.0400.000.171b
    katGrpoB315+444AGC-ACC+ACC-ATC丝氨酸-苏氨酸+苏氨酸-异亮氨酸 12.0400.000.171b
    katGrpoB315+437AGC-ACC+AAC-GAC丝氨酸-苏氨酸+天冬酰胺-天冬氨酸 12.0400.000.171b
    katGrpoB315+435AGC-AAC+GAC-GTC丝氨酸-天冬酰胺+天冬氨酸-缬氨酸 12.0400.000.171b
    katGrpoB315+435AGC-ACC+GAC-GTC丝氨酸-苏氨酸+天冬氨酸-缬氨酸 12.0400.000.171b
    katGrpoB315+430AGC-ACC+CTG-CCG丝氨酸-苏氨酸+亮氨酸-脯氨酸 12.0400.000.171b
    katGrpoB315+400AGC-ACC+ACC-GCC丝氨酸-苏氨酸+苏氨酸-丙氨酸 12.0400.000.171b
    katGrpoB461+430CAG-CCG+CTG-CCG谷氨酰胺-脯氨酸+亮氨酸-脯氨酸 12.0400.000.171b
    inhArpoB194+450ATG-ACC+TCG-TTG蛋氨酸-苏氨酸+丝氨酸-亮氨酸 12.0400.000.171b
    ahpCrpoB-81+450C-T+TCG-TTG−+丝氨酸-亮氨酸 12.0410.22 0.5430.461a
    katGrpoB315+445AGC-ACC+CAC-AAC丝氨酸-苏氨酸+组氨酸-天冬酰胺 00.0010.220.904b
    katGrpoB315+445AGC-ACC+CAC-CGC丝氨酸-苏氨酸+组氨酸-精氨酸 00.0010.220.904b
    katGrpoB315+435AGC-AAC+GAC-GGC丝氨酸-天冬酰胺+天冬氨酸-甘氨酸 00.0010.220.904b
    katGrpoB335+431ATC-ACC+AGC-AGG异亮氨酸-苏氨酸+丝氨酸-精氨酸 00.0010.220.904b
    katGrpoB315+445AGC-ACC+CAC-CGC丝氨酸-苏氨酸+组氨酸-精氨酸 00.0010.220.904b
    kasArpoB121+431AGG-AAG+AGC-AGG精氨酸-赖氨酸+丝氨酸-精氨酸 00.0010.220.904b
    合计356
    注:a. 矫正χ2值,b. Fisher精确概率,−. 无数据
    下载: 导出CSV
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  • 收稿日期:  2021-12-12
  • 网络出版日期:  2022-04-06
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