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Frontiers of Medicine

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Front. Med.    2020, Vol. 14 Issue (1) : 51-59    https://doi.org/10.1007/s11684-019-0720-x
RESEARCH ARTICLE
Characteristics of compensatory mutations in the rpoC gene and their association with compensated transmission of Mycobacterium tuberculosis
Shengfen Wang1, Yang Zhou1, Bing Zhao1, Xichao Ou1, Hui Xia1, Yang Zheng1, Yuanyuan Song1, Qian Cheng1, Xinyang Wang1,2, Yanlin Zhao1()
1. National Tuberculosis Reference Laboratory, National Center for Tuberculosis Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China
2. Department of Microbiology, Basic Medicine College, Harbin Medical University, Harbin 150081, China
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Abstract

The aim of this study was to characterize rpoC gene mutations in Mycobacterium tuberculosis (MTB) and investigate the factors associated with rpoC mutations and the relation between rpoC mutations and tuberculosis (TB) transmission. A total of 245 MTB clinical isolates from patients with TB in six provinces and two municipalities in China were characterized based on gene mutations through DNA sequencing of rpoC and rpoB genes, phenotyping via standard drug susceptibility testing, and genotypic profiling by mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) typing. Approximately 36.4% of the rifampin-resistant isolates harbored nonsynonymous mutations in the rpoC gene. Twenty-nine nonsynonymous single mutations and three double mutations were identified. The rpoC mutations at locus 483 (11.3%) were predominant, and the mutations at V483G, W484G, I491V, L516P, L566R, N698K, and A788E accounted for 54.5% of the total detected mutations. Fifteen new mutations in the rpoC gene were identified. Rifampin resistance and rpoB mutations at locus 531 were significantly associated with rpoC mutations. MIRU-VNTR genotype results indicated that 18.4% of the studied isolates were clustered, and the rpoC mutations were not significantly associated with MIRU-VNTR clusters. A large proportion of rpoC mutation was observed in the rifampicin-resistant MTB isolates. However, the findings of this study do not support the association of rpoC mutation with compensated transmissibility.
Keywords tuberculosis      drug resistance      compensatory mutations      transmission     
Corresponding Author(s): Yanlin Zhao   
Just Accepted Date: 19 December 2019   Online First Date: 15 January 2020    Issue Date: 02 March 2020
 Cite this article:   
Shengfen Wang,Yang Zhou,Bing Zhao, et al. Characteristics of compensatory mutations in the rpoC gene and their association with compensated transmission of Mycobacterium tuberculosis[J]. Front. Med., 2020, 14(1): 51-59.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-019-0720-x
https://academic.hep.com.cn/fmd/EN/Y2020/V14/I1/51
Nonsynonymous (s) in the rpoC gene Mutation (s) at codon (s) No. (%) of strains References Mutations in RRDR of rpoB gene
E275G 275 1 (0.7) Not reported H526L
G332R 332 1 (0.7) [14, 16, 21, 22] S531L
G332S 332 1 (0.7) [23, 16] S531L
G388A 388 1 (0.7) [15] H526D
G433C 433 1 (0.7) [15, 22] S531L
M447V 447 1 (0.7) Not reported H526L
V483A 483 1 (0.7) [14–16, 22–24] S531L
V483G 483 16 (10.6) [14–16, 21–24] D516V (1 strain)
S531W (1 strain)
No mutation (1 strain)
S531L (13 strains)
W484G 484 3 (2.0) [15, 16, 19, 22] S531L
D485Y 485 1 (0.7) [14, 16, 22] L511P
I491T 491 1 (0.7) [14, 15, 19, 21, 22] S531L
I491V 491 2 (1.3) [15, 16, 22, 23] S531L
A492V 492 1 (0.7) [15] S531L
L516P 516 2 (1.3) [16, 19, 22, 23] S531L
A521D 521 1 (0.7) [15, 16, 22, 23] S531L
A521V 521 1 (0.7) Not reported S531L
S561P 561 1 (0.7) [15, 22, 24] H526R
L566R 566 2 (1.3) Not reported S522L
N698K 698 3 (2.0) [15, 16, 19, 22] S531L
A701T 701 1 (0.7) Not reported TTC insert between loci 514 and 515
A788E 788 2 (1.3) Not reported H526y
T845A 845 1 (0.7) Not reported H526R
Y921C 921 1 (0.7) Not reported H526Y
D943G 943 1 (0.7) [22] H526N
Y979C 979 1 (0.7) Not reported H526D
I991S 991 1 (0.7) Not reported D516Y
V1039A 1039 1 (0.7) Not reported S531L
S1115L 1115 1 (0.7) Not reported S531L
V1252L 1252 1 (0.7) [16, 22] L533P, F505L
Q1160P, T812I 1160 and 812 1 (0.7) Not reported S531L, L511P
A519D, I997V 519 and 997 1 (0.7) Not reported S531L
E154D, A492P 154 and 492 1 (0.7) Not reported S531L
Tab.1  Profile of nonsynonymous mutations in the rpoC and rpoB genes of rifampin-resistant strains
Fig.1  Schematic of rpoC mutations at different loci of the RRDR of the rpoB gene. rpoC mutations in red indicate that the mutations have not been reported previously, and those in black indicate that the mutations have been reported. Mutations with a blue and yellow background indicate identical mutations and double mutations at the RRDR loci of the rpoB gene, respectively.
Factors No. (%) of isolates Univariate analysis Multivariate analysis
No rpoC mutation rpoC with mutation OR (95%CI) P value for OR Adjusted OR (95% CI) P value for adjusted OR
Age
<30 years 45 (77.59) 13 (22.41) 1.0 1.0
30–60 years 102 (73.91) 36 (26.0) 1.222 (0.592–2.522) 0.5881 1.711 (0.720–4.065) 0.2238
≥60 years 38 (79.17) 10 (20.83) 0.911 (0.359–2.310) 0.8443 1.283 (0.432–3.812) 0.6537
Gender
Male 137 (74.86) 46 (25.14) 1.0 1.0
Female 48 (78.69) 13 (21.31) 0.807 (0.401–1.621) 0.5462 0.835 (0.375–1.862) 0.6600
Treatment history
New 94 (75.20) 31 (24.80) 1.0 1.0
Retreatment 90 (76.27) 28 (23.73) 0.943 (0.524–1.697) 0.8457 0.715 (0.357–1.430) 0.3428
Strain family
Non-Beijing 37 (78.72) 10 (21.28) 1.0 1.0
Beijing 149 (75.25) 49 (24.75) 1.217 (0.564–2.627) 0.6173 0.864 (0.342–2.186) 0.7581
RMP susceptibility
Susceptible 90 (95.74) 4 (4.26) 1.0 1.0
Monoresistant or MDR 64 (62.14) 39 (37.86) 13.706 (4.666–40.263) <0.0001 8.415 (2.658–26.642) 0.0003
Pre-XDR or XDR 32 (66.67) 16 (33.33) 11.246 (3.499–36.141) <0.0001 6.968 (1.901–25.540) 0.0034
rpoB mutation
No mutation or mutation(s) at loci other than locus 531 150 (86.71) 23 (13.29) 1.0 1.0
Point mutation at locus 531 only 36 (50.00) 36 (50.00) 6.522 (3.448–12.334) <0.0001 3.464 (1.700–7.058) 0.0006
Tab.2  Factors associated with nonsynonymous mutations in the rpoC gene
Factors No. (%) of isolates Univariate analysis Multivariate analysis
Not in the VNTR cluster In the VNTR cluster OR (95% CI) P value for OR Adjusted OR
(95% CI)		 P value for adjusted OR
Age
<30 years 45 (77.59) 13 (22.41) 1.0 1.0
30–60 years 102 (73.91) 36 (26.09) 1.088 (0.500–2.364) 0.8322 1.528 (0.657–3.554) 0.3245
≥60years 38 (79.17) 10 (20.83) 0.610 (0.208–1.794) 0.3695 0.787 (0.254–2.442) 0.6789
Gender
Male 151 (82.51) 32 (17.49) 1.0 1.0
Female 48 (78.69) 13 (21.31) 1.278 (0.621–2.630) 0.5053 1.232 (0.576–2.636) 0.5905
Treatment history
New 97 (77.60) 28 (22.40) 1.0 1.0
Retreatment 101 (85.59) 17 (14.41) 0.583 (0.300–1.133) 0.1113 0.500 (0.245–1.023) 0.0578
Strain family
Non-Beijing 43 (91.49) 4 (8.51) 1.0 1.0
Beijing 157 (79.29) 41 (20.71) 2.807 (0.953–8.270) 0.0612 2.401 (0.787–7.323) 0.1238
RMP phenotype
RMP sensitive 82 (87.23) 12 (12.77) 1.0 1.0
Monoresistant or MDR 82 (79.61) 21 (20.39) 1.750 (0.808–3.789) 0.1556 1.457 (0.596–3.562) 0.4091
Pre-XDR or XDR 36 (75.00) 12 (25.00) 2.278 (0.934–5.552) 0.0702 2.133 (0.739–6.156) 0.1613
rpoB mutation
No mutation or mutation(s) at locus other than locus 531 145 (83.82) 28 (16.18) 1.0 1.0
Point mutation at locus 531 only 55 (76.39) 17 (23.61) 1.601 (0.813–3.153) 0.1735 1.109 (0.479–2.567) 0.8095
rpoC mutation
No rpoC mutation 156 (83.87) 30 (16.13) 1.0 1.0
rpoC mutation 44 (74.58) 15 (25.42) 1.773 (0.877–3.585) 0.1111 1.362 (0.609–3.047) 0.4519
Tab.3  Logistic regression analysis for risk factors associated with MIRU-VNTR clusters
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