浙江省结核分枝杆菌耐药突变特征及其与基因型相关性分析

doi:10.19982/j.issn.1000-6621.20220224

中国防痨杂志 ›› 2022, Vol. 44 ›› Issue (11): 1126-1134.doi: 10.19982/j.issn.1000-6621.20220224

浙江省结核分枝杆菌耐药突变特征及其与基因型相关性分析

吴坤阳¹, 陆烨玮², 张明五¹, 朱业蕾¹, 李相辰², 潘军航¹, 王晓萌¹, 王蔚³, 江敏敏⁴, 彭小军², 王炜欣², 高俊顺², 柳正卫¹()

¹浙江省疾病预防控制中心结核病预防控制所结核病实验室,杭州 310051
²杭州广科安德生物科技有限公司生物信息部,杭州 311215
³嘉兴市第一医院检验科,嘉兴 314001
⁴嘉善县第一人民医院检验科,嘉兴 314199

收稿日期:2022-06-08 出版日期:2022-11-10 发布日期:2022-11-03
通信作者: 柳正卫 E-mail:zhwliu@cdc.zj.cn
基金资助:
浙江省医药卫生科技计划项目(2020keyan512)

Analysis on characteristic of drug resistance-associated gene mutations and the correlation with genotypes among Mycobacterium tuberculosis isolates in Zhejiang Province

Wu Kunyang¹, Lu Yewei², Zhang Mingwu¹, Zhu Yelei¹, Li Xiangchen², Pan Junhang¹, Wang Xiaomeng¹, Wang Wei³, Jiang Minmin⁴, Peng Xiaojun², Wang Weixin², Gao Junshun², Liu Zhengwei¹()

¹Laboratory for Department of TB Control and Prevention, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou 310051, China
²Department of Bioinformatics, Cosmos Wisdom Biotech Co., Ltd., Hangzhou 311215, China
³Department of Clinical Laboratory, the First Hospital of Jiaxing, Jiaxing 314001, China
⁴Department of Clinical Laboratory, the First People’s Hospital of Jiashan, Jiaxing 314199, China

Received:2022-06-08 Online:2022-11-10 Published:2022-11-03
Contact: Liu Zhengwei E-mail:zhwliu@cdc.zj.cn
Supported by:
Zhejiang Provincial Medical and Health Science and Technology Plan Project(2020keyan512)

摘要/Abstract

摘要：

目的: 评价全基因组测序(whole-genome sequencing,WGS)对浙江省结核分枝杆菌(Mycobacterium tuberculosis,MTB)耐药相关基因突变特征及其与基因型相关性的耐药分析和检测效能。方法: 对2018—2019年浙江省第五次结核病耐药监测项目收集的808株MTB菌株进行14种抗结核药物的WGS分析。鉴定菌株的基因型及耐药相关基因突变,并对二者相关性,以及WGS检测异烟肼的药物敏感性试验(简称“药敏试验”)结果与表型药敏试验结果的一致性进行分析。结果: 808株MTB菌株中,153株对11种抗结核药物(异烟肼、利福平、乙胺丁醇、吡嗪酰胺、链霉素、氟喹诺酮类、阿米卡星、卡那霉素、卷曲霉素、乙硫异烟胺、对氨基水杨酸)发生了耐药相关基因突变,总突变率为18.9%。主要耐药突变类型分别为katG-315-S/T[异烟肼,60.0%(45/75)]、rpoB-450-S/L[利福平,57.1%(16/28)]、embB-306-M/V[乙胺丁醇,43.8%(7/16)]、rpsL-43-K/R[链霉素,65.5%(36/55)]、gyrA-94-D/G[氟喹诺酮类,36.6%(15/41)]、rrs-1402-C/A(阿米卡星,3/3)、rrs-1402-C/A(卡那霉素,3/4)、rrs-1402-C/A(卷曲霉素,3/3)、inhA-15-C/T[乙硫异烟胺,65.0%(13/20)]、thyA-75-H/N(对氨基水杨酸,7/8)。rpsL基因和katG-315位点在北京基因型中的耐药突变率[均为6.8%(40/586)]均明显高于二者在非北京基因型中的突变率[0.0%(0/222)和3.2%(7/222)],差异均有统计学意义(χ²=15.943,P=0.000;χ²=3.964,P=0.046)。WGS耐药性分析对于异烟肼的检测敏感度、特异度、阳性预测值、阴性预测值、一致率和Kappa值分别为87.5%(49/56)、98.0%(680/694)、77.8%(49/63)、99.0%(680/687)、97.2%(729/750)和0.808。结论: 浙江省MTB菌株对11种抗结核药物耐药相关基因突变以katG、rpoB、embB、pncA、rpsL、gyrA、rrs、thyA、inhA基因上的突变为主,其中rpsL基因、katG-315和rpsL-43位点突变与北京基因型相关。WGS耐药性分析对于异烟肼具有全面的耐药检测性能,但对个别基因突变位点的检测性能较弱。

关键词: 分枝杆菌,结核, 抗药物性, 序列分析,DNA, 突变, 基因型

Abstract:

Objective: To evaluate the drug resistance analysis and detection performance of whole-genome sequencing (WGS) on the characteristic of drug resistance-associated gene mutations and its correlation with genotypes among Mycobacterium tuberculosis (MTB) isolates in Zhejiang Province. Methods: WGS analysis of 14 drugs was performed on 808 MTB strains collected from the fifth tuberculosis drug resistance surveillance project in Zhejiang Province from 2018 and 2019. MTB genotypes and drug resistance-related gene mutations were identified, meanwhile, their relationship and the consistency of WGS drug susceptibility test results and phenotypic drug susceptibility test results of isoniazid were analyzed. Results: Of the 808 MTB strains, 153 were identified with drug-resistant gene mutations related to 11 anti-tuberculosis drugs (isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, fluoroquinolones, amikacin, kanamycin, capreomycin, ethionamide, para-aminosalicylic acid) and the overall mutation rate was 18.9%. The major drug resistance-associated gene mutation types were katG-315-S/T (isoniazid, 60.0% (45/75)), rpoB-450-S/L (rifampicin, 57.1% (16/28)), embB-306-M/V (ethambutol, 43.8% (7/16)), rpsL-43-K/R (streptomycin, 65.5% (36/55)), gyrA-94-D/G (fluoroquinolones, 36.6% (15/41)), rrs-1402-C/A (amikacin, 3/3), rrs-1402-C/A (kanamycin, 3/4), rrs-1402-C/A (capreomycin, 3/3), inhA-15-C/T (ethionamide, 65.0% (13/20)) and thyA-75-H/N (para-aminosalicylic acid, 7/8). Drug resistance-associated mutations on rpsL gene were detected only in Beijing genotype strains (6.8% (40/586) vs. 0.0% (0/222), χ²=15.943, P=0.000). The mutation rate of katG-315 was higher in Beijing genotype strains (6.8% (40/586)) than non-Beijing genotype strains (3.2% (7/222)) and the difference was statistically significant (χ²=3.964, P=0.046). The sensitivity, specificity, positive predictive value, negative predictive value, consistency rate and Kappa value of the WGS drug resistance profiling method for isoniazid were 87.5% (49/56), 98.0% (680/694), 77.8% (49/63), 99.0% (680/687), 97.2% (729/750) and 0.808, respectively. Conclusion: The major drug resistance-associated gene mutations of 11 drugs were on katG, rpoB, embB, pncA, rpsL, gyrA, rrs, thyA and inhA among Zhejiang Province MTB strains. Mutations on rpsL, katG-315 and rpsL-43 were related with Beijing genotypes. The WGS drug resistance profiling method has comprehensive detection performance for isoniazid, but the performance of some drug-resistant gene mutations is poor.

Key words: Mycobacterium tuberculosis, Drug resistance,bacterial, Sequence analysis,DNA, Mutation, Genotype

中图分类号:

吴坤阳, 陆烨玮, 张明五, 朱业蕾, 李相辰, 潘军航, 王晓萌, 王蔚, 江敏敏, 彭小军, 王炜欣, 高俊顺, 柳正卫. 浙江省结核分枝杆菌耐药突变特征及其与基因型相关性分析[J]. 中国防痨杂志, 2022, 44(11): 1126-1134. doi: 10.19982/j.issn.1000-6621.20220224

Wu Kunyang, Lu Yewei, Zhang Mingwu, Zhu Yelei, Li Xiangchen, Pan Junhang, Wang Xiaomeng, Wang Wei, Jiang Minmin, Peng Xiaojun, Wang Weixin, Gao Junshun, Liu Zhengwei. Analysis on characteristic of drug resistance-associated gene mutations and the correlation with genotypes among Mycobacterium tuberculosis isolates in Zhejiang Province[J]. Chinese Journal of Antituberculosis, 2022, 44(11): 1126-1134. doi: 10.19982/j.issn.1000-6621.20220224

图/表 6

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参考文献 27

[1]	World Health Organization. Global tuberculosis report 2021. Geneva: World Health Organization, 2021.
[2]	陈松华, 吴蓓蓓, 柳正卫, 等. 浙江省结核病耐药状况分析. 预防医学, 2016, 28(8): 757-761,765. doi: 10.19485/j.cnki.issn1007-0931.2016.08.001. doi: 10.19485/j.cnki.issn1007-0931.2016.08.001
[3]	Kizny Gordon A, Marais B, Walker TM, et al. Clinical and public health utility of Mycobacterium tuberculosis whole genome sequencing. Int J Infect Dis, 2021, 113 Suppl 1: S40-S42. doi: 10.1016/j.ijid.2021.02.114. doi: 10.1016/j.ijid.2021.02.114 pmid: 33716192
[4]	张洁, 任怡宣, 潘丽萍, 等. 全基因组测序在结核分枝杆菌研究中的应用. 中国防痨杂志, 2020, 42(7): 737-740. doi: 10.3969/j.issn.1000-6621.2020.07.017. doi: 10.3969/j.issn.1000-6621.2020.07.017
[5]	Meehan CJ, Goig GA, Kohl TA, et al. Whole genome sequencing of Mycobacterium tuberculosis: current standards and open issues. Nat Rev Microbiol, 2019, 17(9): 533-545. doi: 10.1038/s41579-019-0214-5. doi: 10.1038/s41579-019-0214-5 pmid: 31209399
[6]	Cohen KA, Manson AL, Desjardins CA, et al. Deciphering drug resistance in Mycobacterium tuberculosis using whole-genome sequencing: progress, promise, and challenges. Genome Med, 2019, 11(1):45. doi: 10.1186/s13073-019-0660-8. doi: 10.1186/s13073-019-0660-8 URL
[7]	中国防痨协会. 结核病实验室检验规程. 北京: 人民卫生出版社, 2015:59-65.
[8]	Chen S, Zhou Y, Chen Y, et al. fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics, 2018, 34(17):i884-i890. doi: 10.1093/bioinformatics/bty560. doi: 10.1093/bioinformatics/bty560 URL
[9]	Phelan JE, O’Sullivan DM, Machado D, et al. Integrating informatics tools and portable sequencing technology for rapid detection of resistance to anti-tuberculous drugs. Genome Med, 2019, 11(1):41. doi: 10.1186/s13073-019-0650-x. doi: 10.1186/s13073-019-0650-x pmid: 31234910
[10]	World Health Organization. GLASS whole-genome sequencing for surveillance of antimicrobial resistance. Geneva: World Health Organization, 2020.
[11]	Walker TM, Kohl TA, Omar SV, et al. Whole-genome sequencing for prediction of Mycobacterium tuberculosis drug susceptibility and resistance: a retrospective cohort study. Lancet Infect Dis, 2015, 15(10):1193-1202. doi: 10.1016/S1473-3099(15)00062-6. doi: 10.1016/S1473-3099(15)00062-6 URL
[12]	Chen X, He G, Wang S, et al. Evaluation of Whole-Genome Sequence Method to Diagnose Resistance of 13 Anti-tuberculosis Drugs and Characterize Resistance Genes in Clinical Multi-Drug Resistance Mycobacterium tuberculosis Isolates From China. Front Microbiol, 2019, 10:1741. doi: 10.3389/fmicb.2019.01741. doi: 10.3389/fmicb.2019.01741 URL
[13]	World Health Organization. Target product profile for next-generation drug-susceptibility testing at peripheral centres. Geneva: World Health Organization, 2021.
[14]	Hillemann D, Rüsch-Gerdes S, Boehme C, et al. Rapid molecular detection of extrapulmonary tuberculosis by the automated GeneXpert MTB/RIF system. J Clin Microbiol, 2011, 49(4):1202-1205. doi: 10.1128/JCM.02268-10. doi: 10.1128/JCM.02268-10 pmid: 21270230
[15]	Meaza A, Kebede A, Yaregal Z, et al. Evaluation of genotype MTBDRplus VER 2.0 line probe assay for the detection of MDR-TB in smear positive and negative sputum samples. BMC Infect Dis, 2017, 17(1):280. doi: 10.1186/s12879-017-2389-6. doi: 10.1186/s12879-017-2389-6 pmid: 28415989
[16]	Jian J, Yang X, Yang J, et al. Evaluation of the GenoType MTBDRplus and MTBDRsl for the detection of drug-resistant Mycobacterium tuberculosis on isolates from Beijing, China. Infect Drug Resist, 2018, 11:1627-1634. doi: 10.2147/IDR.S176609. doi: 10.2147/IDR.S176609 URL
[17]	罗丹, 覃慧芳, 叶婧, 等. 广西壮族自治区结核分枝杆菌耐药基因突变特征及其与基因型的相关性分析. 中国防痨杂志, 2021, 43(6): 596-601. doi: 10.3969/j.issn.1000-6621.2021.06.013. doi: 10.3969/j.issn.1000-6621.2021.06.013
[18]	洪创跃, 杨婷婷, 李金莉, 等. 深圳市耐多药结核分枝杆菌耐药基因突变特征分析. 中国防痨杂志, 2020, 42(6): 583-589. doi: 10.3969/j.issn.1000-6621.2020.06.009. doi: 10.3969/j.issn.1000-6621.2020.06.009
[19]	高敏, 杨婷婷, 李桂莲, 等. 基于全基因组测序的我国耐多药结核分枝杆菌耐药突变特征分析. 中华流行病学杂志, 2020, 41(5): 770-775. doi: 10.3760/cma.j.cn112338-20191111-00800. doi: 10.3760/cma.j.cn112338-20191111-00800
[20]	田丽, 周伟, 黄星, 等. 中国异烟肼耐药结核分枝杆菌基因突变特征分析. 中国防痨杂志, 2022, 44(4): 354-361. doi: 10.19982/j.issn.1000-6621.20210573. doi: 10.19982/j.issn.1000-6621.20210573
[21]	Lempens P, Meehan CJ, Vandelannoote K, et al. Isoniazid resistance levels of Mycobacterium tuberculosis can largely be predicted by high-confidence resistance-conferring mutations. Sci Rep, 2018, 8(1):3246. doi: 10.1038/s41598-018-21378-x. doi: 10.1038/s41598-018-21378-x URL
[22]	Zhang D, Liu B, Wang Y, et al. Rapid molecular screening for multidrug-resistant tuberculosis in a resource-limited region of China. Trop Med Int Health, 2014, 19(10):1259-1266. doi: 10.1111/tmi.12359. doi: 10.1111/tmi.12359 pmid: 25040060
[23]	Ye M, Yuan W, Molaeipour L, et al. Antibiotic heteroresistance in Mycobacterium tuberculosis isolates: a systematic review and meta-analysis. Ann Clin Microbiol Antimicrob, 2021, 20(1):73. doi: 10.1186/s12941-021-00478-z. doi: 10.1186/s12941-021-00478-z URL
[24]	Javed H, Bakuła Z, Pleń M, et al. Evaluation of Genotype MTBDRplus and MTBDRsl Assays for Rapid Detection of Drug Resistance in Extensively Drug-Resistant Mycobacterium tuberculosis Isolates in Pakistan. Front Microbiol, 2018, 9:2265. doi: 10.3389/fmicb.2018.02265. doi: 10.3389/fmicb.2018.02265 URL
[25]	Dantas NGT, Suffys PN, Carvalho WDS, et al. Correlation between the BACTEC MGIT 960 culture system with Genotype MTBDRplus and TB-SPRINT in multidrug resistant Mycobacterium tuberculosis clinical isolates from Brazil. Mem Inst Oswaldo Cruz, 2017, 112(11):769-774. doi: 10.1590/0074-02760170062. doi: 10.1590/0074-02760170062 URL
[26]	Li D, Hu Y, Werngren J, et al. Multicenter Study of the Emergence and Genetic Characteristics of Pyrazinamide-Resis-tant Tuberculosis in China. Antimicrob Agents Chemother, 2016, 60(9):5159-5166. doi: 10.1128/AAC.02687-15. doi: 10.1128/AAC.02687-15 URL
[27]	Huang H, Ding N, Yang T, et al. Cross-sectional Whole-genome Sequencing and Epidemiological Study of Multidrug-resistant Mycobacterium tuberculosis in China. Clin Infect Dis, 2019, 69(3):405-413. doi: 10.1093/cid/ciy883. doi: 10.1093/cid/ciy883 URL

药品	耐药菌株株数	耐药率(%)	耐药基因	突变菌株数	突变率(%)
异烟肼	75	9.3	katG	54	72.0
			inhA	14	18.7
			inhA+katG	2	2.7
			ahpC+katG	2	2.7
			ahpC	2	2.7
			ahpC+inhA+katG	1	1.3
利福平	28	3.5	rpoB	26	92.9
			rpoB+rpoC	2	7.1
乙胺丁醇	16	2.0	embB	14	87.5
			embA+embB	1	6.3
			embA	1	6.3
吡嗪酰胺	12	1.5	pncA	12	100.0
链霉素	55	6.8	rpsL	40	72.7
			rrs	12	21.8
			gid	2	3.6
			gid+rrs	1	1.8
氟喹诺酮类	41	5.1	gyrA	36	87.8
			gyrB	4	9.8
			gyrA+gyrB	1	2.4
阿米卡星	3	0.4	rrs	3	100.0
卡那霉素	4	0.5	rrs	3	75.0
			eis	1	25.0
卷曲霉素	3	0.4	rrs	3	100.0
药品	耐药菌株株数	耐药率(%)	耐药基因	突变菌株数	突变率(%)
乙硫异烟胺	20	2.5	inhA	16	80.0
			ethA	3	15.0
			ethA+inhA	1	5.0
对氨基水杨酸	8	1.0	thyA	7	87.5
			folC	1	12.5

药品	耐药菌株数	耐药率 (%)	突变类型	突变菌株数	突变率 (%)	平均测序深度	平均突变频率 (%)
异烟肼	75	9.3	katG-315-S/T	45	60.0	457	99.3
			inhA-15-C/T	13	17.3	423	94.5
			ahpC启动子-48-G/A	4	5.3	572	96.8
			其他	20	26.6	375	95.5
利福平	28	3.5	rpoB-450-S/L	16	57.1	385	97.7
			rpoB-452-L/P	4	14.3	393	82.5
			rpoB-430-L/P	4	14.3	329	100.0
			其他	9	32.1	470	99.9
乙胺丁醇	16	2.0	embB-306-M/V	7	43.8	396	95.5
			embB-306-M/I	2	12.5	381	100.0
			embB-354-D/A	2	12.5	491	99.9
			其他	6	37.5	483	90.6
吡嗪酰胺	12	1.5	-	-	-	526	99.6
链霉素	55	6.8	rpsL-43-K/R	36	65.5	569	99.8
			rrs-514-A/C	6	10.9	418	97.1
			rpsL-88-K/R	3	5.5	473	100.0
			其他	8	14.6	329	64.0
氟喹诺酮类	41	5.1	gyrA-94-D/G	15	36.6	473	92.9
			gyrA-90-A/V	12	29.3	491	94.5
			gyrA-94-D/N	7	17.1	572	98.7
			其他	10	24.4	495	65.4
阿米卡星	3	0.4	rrs-1402-C/A	3	3/3	249	21.7
			rrs-1484-G/T	2	2/3	290	19.3
卡那霉素	4	0.5	rrs-1402-C/A	3	3/4	249	21.7
			rrs-1484-G/T	2	2/4	290	19.3
			eis启动子-10-G/A	1	1/4	547	100.0
卷曲霉素	3	0.4	rrs-1402-C/A	3	3/3	249	21.7
			rrs-1484-G/T	2	2/3	290	19.3
乙硫异烟胺	20	2.5	inhA-15-C/T	13	65.0	423	94.5
			其他	8	40.0	469	96.6
对氨基水杨酸	8	1.0	thyA-75-H/N	7	7/8	736	99.8
			folC-150-S/G	1	1/8	613	97.4

耐药基因	北京基因型 (586株)	非北京基因型 (222株)	χ²值	P值
katG	46(7.8)	13(5.9)	0.946	0.331
rpsL	40(6.8)	0(0.0)	15.943	0.000
gyrA	26(4.4)	11(5.0)	0.099	0.753
rpoB	24(4.1)	4(1.8)	2.532	0.133

突变位点	北京基因型 (586株)	非北京基因型 (222株)	χ²值	P值
katG-315	40(6.8)	7(3.2)	3.964	0.046
rpsL-43	36(6.1)	0(0.0)	14.274	0.000
gyrA-94	18(3.1)	5(2.3)	0.391	0.532
rpoB-450	15(2.6)	1(0.5)	3.691	0.085

突变位点	表型药敏试验结果	不一致株数	比例(%)	突变菌株数	不一致率(%)
katG-315-S/T	敏感	5	23.8	43	11.6
ahpC启动子-48-G/A	敏感	3	14.3	4	3/4
inhA-15-C/T	敏感	2	9.5	12	16.7
katG-110-A/V	敏感	1	4.8	2	-
katG-127-Q/P	敏感	1	4.8	1	-
katG-258-N/S	敏感	1	4.8	1	-
katG-335-I/V	敏感	1	4.8	1	-
katG-337-Y/C	敏感	1	4.8	1	-
katG-607-E/K	敏感	1	4.8	1	-
野生型	耐药	7	33.3	-	-

浙江省结核分枝杆菌耐药突变特征及其与基因型相关性分析

Analysis on characteristic of drug resistance-associated gene mutations and the correlation with genotypes among Mycobacterium tuberculosis isolates in Zhejiang Province

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检测方法	表型药敏试验(株)		合计 (株)	敏感度 (%)	特异度 (%)	阳性预测值 (%)	阴性预测值 (%)	一致率 (%)	Kappa值
检测方法	耐药	敏感	合计 (株)	敏感度 (%)	特异度 (%)	阳性预测值 (%)	阴性预测值 (%)	一致率 (%)	Kappa值
全基因组测序				87.5	98.0	77.8	99.0	97.2	0.808
耐药	49	14	63
敏感	7	680	687
合计	56	694	750

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