河南省耐多药结核菌耐药相关基因的分子流行病学研究
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摘要
中国是全球22个结核病高负担国家之一,患病人数仅次于印度居世界第二。我国的耐药结核病流行状况也很严重,耐多药(MDR)结核的流行比例为9.3%,约是世界平均水平的2倍。耐多药结核病治疗周期长、药物副作用大,而且治愈率低、死亡率高。因此,耐多药结核病的控制对于中国当前结核病的防治具有重要意义。
早期快速诊断结核分枝杆菌的耐药性有利于耐多药结核病的治疗和控制。和基于培养的药敏检测方法相比,基于分子生物学的药敏检测方法具有快速、敏感和成本较低的优势。目前,已有商品化的产品INNO-LiPARif.TB (Innogenetics, Belgium)和GenoType MTBDR plus (Genotype MTBDR; Hain Lifescience, Nehren, Germany)被WHO认为可以用于结核耐多药性的快速诊断。但是由于不同地区流行菌株的耐药相关基因突变频率和类型不同,这些工具检测耐药性的灵敏度和特异度在不同地区也不同。因此,对于不同地区菌株的耐药相关基因突变频率和类型的全面了解,有利于这类新的诊断技术的开发和广泛应用。
在中国对耐药结核菌,特别是耐多药结核菌的耐药相关基因的突变频率和突变类型进行的研究还很少。我们试图通过改善的、全面的结核分支杆菌耐药相关基因的研究,对河南省耐多药结核菌4个一线抗结核药耐药相关基因的突变频率和突变类型进行详细描述,并对各个耐药相关基因的的变异规律进行了深入的探讨,为开发适合该地区耐多药结核菌的高灵敏度和特异度的诊断方法提供更多的数据。
本研究中共收集来自河南省不同地区的115株耐多药结核菌和22株对一线4个抗结核药全敏感的菌株。使用WHO推荐的比例法检测菌株对一线4个抗结核药的药物敏感性,获得菌株的耐药特征。
我们检测了所有已知的一线4个抗结核药物的9个耐药相关基因的编码区全长和部分启动子区,以期能获得相关基因突变频率和突变类型的更全面信息。通过对河南115株耐多药结核菌4个一线抗结核药的耐药相关基因突变特征的全面分析,我们发现：
(1)本研究利福平和异烟肼耐药相关基因所有的已知突变的总突变频率没有明显改变,如：本研究rpoB所有的已知突变的总突变频率为97.3%,与多数研究报道的95%到98%一致。此外,MDR菌株中各耐药相关突变位点的突变频率的顺位没有改变。如：rpoB531>rpoB526>rpoB516,rpsL43>rpsL88>rrs513。
(2)同一地区,在MDR菌株较多或全部为MDR菌株的研究中,多个耐药相关基因的主要突变位点的突变频率高于MDR菌株较少或单耐药菌株的研究,这些突变位点有rpoV531、katG315、embB306、rpsL43。此外,有的耐药相关基因的突变,如：embB306和rpsL 43,在MDR菌株中会出现在该突变对应耐药性的敏感菌株。
(3)共发现53个新突变位点,16个新突变类型,这些新突变位点和类型在MDR结核菌的耐药发生中的作用需要进一步研究。
此外,我们还利用已获得的耐多药结核菌耐药相关基因突变特征及其耐药特征数据,对embB基因突变(包括embB306突变)和MDR结核菌耐药性间的关系进行了分析,得到了如下结论：
(1)在MDR结核菌中,embB基因上的突变,包括embB306突变,和乙胺丁醇耐药统计学上相关。单独检测embB306突变预测乙胺丁醇耐药灵敏度不高(62.7%),通过检测embB基因所有突变,可以提高灵敏度至89.6%。这提示embB基因上多个位点均可能参与了乙胺丁醇的耐药发生,大多数突变集中在300到500密码子间。某些对乙胺丁醇敏感的MDR菌株发生embB基因突变(包括embB306突变),这与多数研究结论一致,表明embB基因突变不仅和乙胺丁醇耐药相关,还可能与MDR相关。
(2)总体上embB306位点突变菌株比例随耐药数目增加而增加,趋势卡方检验显示相关性有统计学显著性。但耐3药组embB306位点突变菌株比例低于耐2药组,这可能是因为本研究中耐链霉素的MDR菌株发生突变的比例(17.9%)较低；也可能是因为耐2药(MDR)组样本量较少而影响了统计分析的稳定性。同样,embB基因各位点总和突变与耐药数目增加的相关性有统计学显著性,其中发生embB497突变的MDR菌株在耐4药组明显多于耐3药组,提示embB基因其他位点突变可能也有随耐药数目增加而增加的趋势。
(3)耐4药组菌株中有90.2%发生embB基因突变。通过检测embB基因4个位点的突变(embB306、embB354、embB406和embB497)可以发现83.6%的一线4重耐药菌株,灵敏度较高,用于一线4重耐药性初步筛选有很好的潜在应用价值,特别适用于像河南这种耐一线4个抗结核药在MDR结核菌中比例(53%)较高的地区。
China is one of the tuberculosis (TB) high burden countries reported by WHO and the incidence number of TB in China ranks the second in the world, following India. The epidemic of MDR TB is severe in China either. A recent study reported that 9.3% of all TB cases in China are MDR, almost twice higher than the world's average MDR prevalence. MDR TB indicates longer treatment, more adverse effect and low treatment outcome. Thus, MDR TB control is important for the management of TB in China.
Novel tools are urgently needed for the rapid, reliable detection of multi-drug resistant (MDR) and even extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis. To develop such tools, we need information about the frequency and distribution of the mycobacterial mutations and genotypes that are associated with phenotypic drug resistance. In a population-based study, we collected 115 MDR isolates resistant to at least rifampin, isoniazid and 22 pan-susceptible isolates from TB patients in Henan, China. The culture-based proportion method was used as drug susceptibility testing (DST) and for each isolate, four anti-tuberculosis drug susceptibility(RIF, INH, EMB, STR) were identified. We detected mutations within nine known drug resistance related genes, including:rpoB, katG, inhA, oxyR, ahpC, kasA, embB, rpsL and rrs. The full length ORFs and the partial region of promoters were amplified and sequenced for fully understanding the mutation pattern of these above genes
After comprehensive analysis of the mutation pattern and the drug resistance spectrum of study isolates, several conclusion can be drawn:
1. The priorities of frequency of main mutation locus in drug resistance related genes are not changed, e.g.:rpoB531>rpoB526> rpoB516,rpsL43> rpsL88> rrs513. And in one region, the frequencies of all mutation locus in drug resistance related genes are not changed.
2. In one region, there are higher frequencies of main mutation locus reported by the studies with more MDR isolates, e.g.:rpoB531, katG315, embB306, rpsL43.
3. Some drug sensitive but MDR isolates may carry mutations of some drug related genes, e.g.:embB306 and rpsL 43.
In addition, based on the data of mutation pattern and drug resistance pattern, we analyzed the association between embB gene mutations and drug resistance of MDR isolates. There are the conclusions as follows:
1. embB306 is not the single cause of EMB resistance, but it is a useful candidate marker for the EMB resistance analysis and the sensitivity of EMB resistance prediction can be improved to 89.6% by combining more embB sites.
2. All embB specific mutations among drug resistant isolates, can be candidate markers for broad drug resistance prediction. A total of 90.2% isolates concurrent resistant to four first line drugs carry mutation at embB mutation sites.
3. A 576bp fragment of embB covers four mutation sites of embB306,354,406 and 497 can detect 83.6% of these four drug resistant isolates which may leads the development of a simple and rapid molecular test to detect four first-line drugs resistance in Henan, China
早期快速诊断结核分枝杆菌的耐药性有利于耐多药结核病的治疗和控制。和基于培养的药敏检测方法相比,基于分子生物学的药敏检测方法具有快速、敏感和成本较低的优势。目前,已有商品化的产品INNO-LiPARif.TB (Innogenetics, Belgium)和GenoType MTBDR plus (Genotype MTBDR; Hain Lifescience, Nehren, Germany)被WHO认为可以用于结核耐多药性的快速诊断。但是由于不同地区流行菌株的耐药相关基因突变频率和类型不同,这些工具检测耐药性的灵敏度和特异度在不同地区也不同。因此,对于不同地区菌株的耐药相关基因突变频率和类型的全面了解,有利于这类新的诊断技术的开发和广泛应用。
在中国对耐药结核菌,特别是耐多药结核菌的耐药相关基因的突变频率和突变类型进行的研究还很少。我们试图通过改善的、全面的结核分支杆菌耐药相关基因的研究,对河南省耐多药结核菌4个一线抗结核药耐药相关基因的突变频率和突变类型进行详细描述,并对各个耐药相关基因的的变异规律进行了深入的探讨,为开发适合该地区耐多药结核菌的高灵敏度和特异度的诊断方法提供更多的数据。
本研究中共收集来自河南省不同地区的115株耐多药结核菌和22株对一线4个抗结核药全敏感的菌株。使用WHO推荐的比例法检测菌株对一线4个抗结核药的药物敏感性,获得菌株的耐药特征。
我们检测了所有已知的一线4个抗结核药物的9个耐药相关基因的编码区全长和部分启动子区,以期能获得相关基因突变频率和突变类型的更全面信息。通过对河南115株耐多药结核菌4个一线抗结核药的耐药相关基因突变特征的全面分析,我们发现：
(1)本研究利福平和异烟肼耐药相关基因所有的已知突变的总突变频率没有明显改变,如：本研究rpoB所有的已知突变的总突变频率为97.3%,与多数研究报道的95%到98%一致。此外,MDR菌株中各耐药相关突变位点的突变频率的顺位没有改变。如：rpoB531>rpoB526>rpoB516,rpsL43>rpsL88>rrs513。
(2)同一地区,在MDR菌株较多或全部为MDR菌株的研究中,多个耐药相关基因的主要突变位点的突变频率高于MDR菌株较少或单耐药菌株的研究,这些突变位点有rpoV531、katG315、embB306、rpsL43。此外,有的耐药相关基因的突变,如：embB306和rpsL 43,在MDR菌株中会出现在该突变对应耐药性的敏感菌株。
(3)共发现53个新突变位点,16个新突变类型,这些新突变位点和类型在MDR结核菌的耐药发生中的作用需要进一步研究。
此外,我们还利用已获得的耐多药结核菌耐药相关基因突变特征及其耐药特征数据,对embB基因突变(包括embB306突变)和MDR结核菌耐药性间的关系进行了分析,得到了如下结论：
(1)在MDR结核菌中,embB基因上的突变,包括embB306突变,和乙胺丁醇耐药统计学上相关。单独检测embB306突变预测乙胺丁醇耐药灵敏度不高(62.7%),通过检测embB基因所有突变,可以提高灵敏度至89.6%。这提示embB基因上多个位点均可能参与了乙胺丁醇的耐药发生,大多数突变集中在300到500密码子间。某些对乙胺丁醇敏感的MDR菌株发生embB基因突变(包括embB306突变),这与多数研究结论一致,表明embB基因突变不仅和乙胺丁醇耐药相关,还可能与MDR相关。
(2)总体上embB306位点突变菌株比例随耐药数目增加而增加,趋势卡方检验显示相关性有统计学显著性。但耐3药组embB306位点突变菌株比例低于耐2药组,这可能是因为本研究中耐链霉素的MDR菌株发生突变的比例(17.9%)较低；也可能是因为耐2药(MDR)组样本量较少而影响了统计分析的稳定性。同样,embB基因各位点总和突变与耐药数目增加的相关性有统计学显著性,其中发生embB497突变的MDR菌株在耐4药组明显多于耐3药组,提示embB基因其他位点突变可能也有随耐药数目增加而增加的趋势。
(3)耐4药组菌株中有90.2%发生embB基因突变。通过检测embB基因4个位点的突变(embB306、embB354、embB406和embB497)可以发现83.6%的一线4重耐药菌株,灵敏度较高,用于一线4重耐药性初步筛选有很好的潜在应用价值,特别适用于像河南这种耐一线4个抗结核药在MDR结核菌中比例(53%)较高的地区。
China is one of the tuberculosis (TB) high burden countries reported by WHO and the incidence number of TB in China ranks the second in the world, following India. The epidemic of MDR TB is severe in China either. A recent study reported that 9.3% of all TB cases in China are MDR, almost twice higher than the world's average MDR prevalence. MDR TB indicates longer treatment, more adverse effect and low treatment outcome. Thus, MDR TB control is important for the management of TB in China.
Novel tools are urgently needed for the rapid, reliable detection of multi-drug resistant (MDR) and even extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis. To develop such tools, we need information about the frequency and distribution of the mycobacterial mutations and genotypes that are associated with phenotypic drug resistance. In a population-based study, we collected 115 MDR isolates resistant to at least rifampin, isoniazid and 22 pan-susceptible isolates from TB patients in Henan, China. The culture-based proportion method was used as drug susceptibility testing (DST) and for each isolate, four anti-tuberculosis drug susceptibility(RIF, INH, EMB, STR) were identified. We detected mutations within nine known drug resistance related genes, including:rpoB, katG, inhA, oxyR, ahpC, kasA, embB, rpsL and rrs. The full length ORFs and the partial region of promoters were amplified and sequenced for fully understanding the mutation pattern of these above genes
After comprehensive analysis of the mutation pattern and the drug resistance spectrum of study isolates, several conclusion can be drawn:
1. The priorities of frequency of main mutation locus in drug resistance related genes are not changed, e.g.:rpoB531>rpoB526> rpoB516,rpsL43> rpsL88> rrs513. And in one region, the frequencies of all mutation locus in drug resistance related genes are not changed.
2. In one region, there are higher frequencies of main mutation locus reported by the studies with more MDR isolates, e.g.:rpoB531, katG315, embB306, rpsL43.
3. Some drug sensitive but MDR isolates may carry mutations of some drug related genes, e.g.:embB306 and rpsL 43.
In addition, based on the data of mutation pattern and drug resistance pattern, we analyzed the association between embB gene mutations and drug resistance of MDR isolates. There are the conclusions as follows:
1. embB306 is not the single cause of EMB resistance, but it is a useful candidate marker for the EMB resistance analysis and the sensitivity of EMB resistance prediction can be improved to 89.6% by combining more embB sites.
2. All embB specific mutations among drug resistant isolates, can be candidate markers for broad drug resistance prediction. A total of 90.2% isolates concurrent resistant to four first line drugs carry mutation at embB mutation sites.
3. A 576bp fragment of embB covers four mutation sites of embB306,354,406 and 497 can detect 83.6% of these four drug resistant isolates which may leads the development of a simple and rapid molecular test to detect four first-line drugs resistance in Henan, China
引文
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