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

  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）。 katG和rpoB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）。 katG＋rpoB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katG＋rpoB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。

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

  Objective  To understand the combined mutation characteristics of isoniazid and rifampicin resistance genes of Mycobacterium tuberculosis in Guangxi and provide a basis for the molecular diagnosis and treatment of multidrug-resistant tuberculosis (MDR-TB).   Methods  A total of 49 MDR strains and 459 fully sensitive strains of M. tuberculosis collected from 30 designated TB treatment institutions in Guangxi during 2017–2018 were selected for whole genome sequencing.   Results  The consistent rate between the MDR phenotype and the combined mutation of genes was 71.43%. The single gene mutation rate and combined gene mutation rate were higher in the MDR strains than in the fully sensitive strains (χ2=5.753, P=0.016; χ2=284.034, P<0.001). The single gene mutation rates of katG and rpoB were higher in the MDR strains than in the fully sensitive strains (χ2=7.524, P=0.006; χ2=4.353, P=0.037). Combined mutations in katG＋rpoB genes were higher in the MDR strains than in the fully sensitive strains (χ2=279.956, P<0.001). Among the distribution of combined gene mutations, mutations at the katG315＋rpoB450 and katG315＋rpoB445 loci accounted for 40.82% (20/49), and the combined mutation rate of gene loci in both forms was higher in the MDR strains than in the fully sensitive strains (χ2=144.232, P<0.001; χ2=19.014, P<0.001).   Conclusion  Detection of combined mutations of resistance genes to isoniazid and rifampicin can be used as an important method for MDR screening in Guangxi. Isoniazid and rifampicin resistance gene mutations of M. tuberculosis in Guangxi were mainly caused by mutations at the loci of katG315, rpoB450 and rpoB445, while the gene combined mutations were mainly in the form of katG＋rpoB. Mutations at the katG315＋rpoB450 and katG315＋rpoB445 loci are the main molecular mechanisms of MDR in Guangxi.