TYPE Original Research

PUBLISHED 06 September 2022

DOI 10.3389/fpubh.2022.976221

Association between IFNGR1

OPEN ACCESS gene polymorphisms and
tuberculosis susceptibility: A
EDITED BY
José Tuells,
University of Alicante, Spain

REVIEWED BY
Shahab Alizadeh,
meta-analysis
Tehran University of Medical
Sciences, Iran
Hongsheng Wang, Liwei Cheng1† , Fan Zhang2† , Ying Wang3 , Jing Chen4*‡ and
Chinese Academy of Medical Sciences
and Peking Union Medical Xiaoping Yuan3*‡
College, China 1
Office of Academic Research, Renmin Hospital of Wuhan University, Wuhan, China, 2 Department
*CORRESPONDENCE of Neurology, Renmin Hospital of Wuhan University, Wuhan, China, 3 Department of Psychiatry,
Xiaoping Yuan Renmin Hospital of Wuhan University, Wuhan, China, 4 Outpatient Department, Renmin Hospital of
[email protected] Wuhan University, Wuhan, China
Jing Chen
[email protected]

†
These authors have contributed The association of IFN-γ receptor 1 (IFNGR1) gene polymorphisms with
equally to this work and share first tuberculosis (TB) susceptibility has not been systematically studied. We
authorship
‡
These authors have contributed
therefore conducted a meta-analysis to assess their association. Literature
equally to this work and share last search was conducted in PubMed, EMBASE, Web of Science, and the Cochrane
authorship Library. Odds ratio (OR) and 95% confidence interval (CI) was pooled by the
SPECIALTY SECTION random-effect model. Statistical analyses were performed using STATA 12.0
This article was submitted to
Infectious Diseases - Surveillance,
software. Fourteen studies involved 7,699 TB cases and 8,289 controls were
Prevention and Treatment, included in this meta-analysis. A significant association was found between
a section of the journal the IFNGR1 rs2234711 polymorphism and TB susceptibility among Africans in
Frontiers in Public Health
dominant model (OR = 1.24, 95%CI:1.01–1.52), and among Asians in allele
RECEIVED 23 June 2022
ACCEPTED 15 August 2022
model (OR = 0.89, 95%CI: 0.79–0.99), homozygote model (OR = 0.82, 95%CI:
PUBLISHED 06 September 2022 0.70–0.98) and additive model (OR = 0.90, 95%CI: 0.83–0.97). In addition,
CITATION a significant association was observed between the IFNGR1 rs7749390
Cheng L, Zhang F, Wang Y, Chen J and polymorphism and TB susceptibility among Africans in allele model (OR =
Yuan X (2022) Association between
IFNGR1 gene polymorphisms and 0.89, 95%CI: 0.82–0.98). No significant association was found between the
tuberculosis susceptibility: A IFNGR1 rs1327474 polymorphism and TB susceptibility. In summary, IFNGR1
meta-analysis.
rs2234711 polymorphism was associated with increased TB susceptibility in
Front. Public Health 10:976221.
doi: 10.3389/fpubh.2022.976221 Africans and decreased TB susceptibility in Asians, while IFNGR1 rs7749390
COPYRIGHT
polymorphism was associated with decreased TB susceptibility in Africans.
© 2022 Cheng, Zhang, Wang, Chen
and Yuan. This is an open-access KEYWORDS
article distributed under the terms of
the Creative Commons Attribution tuberculosis, interferon gamma receptor 1, polymorphism, susceptibility,
License (CC BY). The use, distribution metaanalysis
or reproduction in other forums is
permitted, provided the original
author(s) and the copyright owner(s)
are credited and that the original Introduction
publication in this journal is cited, in
accordance with accepted academic
practice. No use, distribution or
Tuberculosis (TB), a chronic infectious disease caused by the bacterium
reproduction is permitted which does mycobacterium tuberculosis (M.TB), affects several organs, but mostly attacks the lungs
not comply with these terms. (1). According to the World Health Organization, TB is associated with an estimation of
10 million incident cases (2), among which 8.7 million cases are from 30 high-burden

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Cheng et al. 10.3389/fpubh.2022.976221

countries (3), and causes approximately 1.3 million deaths rs7749390, and TB susceptibility; (2) studies had a case-control
worldwide in 2018 (2). Over the past decade, the incidence or cohort design; (3) studies provided odds ratios (ORs) and the
of drug-resistant TB has continued to increase. Globally, corresponding 95% confidence intervals (CIs) for at least for one
4.6% of TB cases are multidrug resistant, and in some model, or provided the allele frequencies to calculate the ORs
areas, this proportion exceeds 25% (4). Therefore, TB remains and 95% CIs. Studies were excluded for the following criteria:
a major public health concern worldwide, especially in (1) were reviews, meta-analysis, or case-reports; (2) provided no
developing countries. data about genotype distribution or allele frequency or ORs; (3)
Many studies have demonstrated that TB susceptibility is used duplicated data.
partly determined by the host genetic background (5–7). In
support of this, differences in the rates of TB occurrence among
ethnicities and families indicate a genetic predisposition to TB Data extraction and quality assessment
susceptibility (8). Interferon-gamma (IFN-γ) is well–known to
play a critical role in the activation of macrophages and dendritic The following data were extracted from the included studies:
cells and influences the innate immune response to certain first author, publication year, country, ethnicity of participants,
contagious agents, including M.TB (9). The interferon-gamma genotyping method, diagnosis assays for detection of TB, sample
receptor 1 (IFNGR1) gene encodes the ligand-binding chain sizes in case groups and control groups, genotype distributions
(alpha) of the IFN-γ receptor, which is located on chromosome and allele frequency or the most fully adjusted ORs and 95%
6q23.3 (10). After binding to IFN-γ, IFNGR1 could regulate the CIs. Two co-authors independently extracted the data from each
cytokine response in Natural killer and T cells to exert their study and any discrepancies were resolved via discussion with
microbicidal functions (11, 12). Animal and in vitro studies the third author.
have demonstrated that IFNGR1 plays a pivotal role in the The methodological quality of the included studies was
progression of TB (13, 14). assessed using the Newcastle-Ottawa Scale (NOS) (31). Studies
Previous studies have investigated the association between with a NOS star of 0–3, 4–6, and 7–9 were considered as
genetic variants of IFNGR1 and TB susceptibility based on the low, moderate, and high quality, respectively. Departure from
hypothesis that defects or variations in IFNGR1 may result the Hardy Weinberg equilibrium (HWE) for the control group
in the increased susceptibility or accelerated progression of in each study was assessed with Pearson’s goodness-of-fit chi-
diverse diseases, such as inflammatory and virus-associated square test with one degree of freedom or was extracted from
disorders (15, 16). Three potentially functional single nucleotide the studies which did not provide genotype distribution.
polymorphisms (SNPs) of the IFNGR1 gene (rs2234711,
rs1327474, and rs7749390) have been investigated to explore
their impact on TB susceptibility by several studies (17–30). Statistical analysis
Nonetheless, the results did not provide consistently significant
associations between these SNPs possibly due to the use of OR was used as a measure of the association between the
sample sizes that did not allow the detection of small genetic IFNGR1 gene polymorphisms and TB susceptibility to combine
effects. Therefore, this meta-analysis was conducted to detect the results. We used the most fully adjusted ORs and 95%CIs
the association of the IFNGR1 rs2234711, rs1327474, rs7749390 from each study for meta-analysis. When the adjusted ORs and
polymorphisms with TB susceptibility. 95%CIs were not provided by the included studies, we used the
gene alle frequencies to compute the crude ORs and 95%CIs.
The overall ORs and corresponding 95%CIs was pooled by the
Methods random-effect model. Heterogeneity across studies was detected
by the Cochran Chi-square (significance level at P < 0.10)
Literature search and Higgins I2 statistic (32, 33). The Begg’s test (34) and the
Egger’s test (35) were used to assess publication bias. We pooled
A comprehensive literature search was conducted in the ORs of associations between each SNP (for instance, the
PubMed, Embase, Web of Science, and the Cochrane Library of rs2234711) with TB susceptibility for six comparison models,
publications up to Apr 20th, 2022. The search terms used were including the dominant model (CC+CT vs. TT), allele model
as follows: (interferon-γ receptor OR interferon-γ receptor 1 OR (C vs. T), homozygote model (CC vs. TT), heterozygote model
IFNGR OR IFNGR1) AND tuberculosis. Further studies were (CT vs. TT), recessive model (CC vs. TT+CT), and additive
identified from the reference lists, related articles and citation model (CC vs. CT vs. TT). Sensitivity analysis was performed by
lists of each of papers identified from the initial searches. individually removing the included studies to assess the stability
The studies included in our meta-analysis met all the of results. Subgroup analysis was conducted to determine
following criteria: (1) studies had to assess the association whether there was an association between the IFNGR1 gene
between IFNGR1 gene polymorphisms rs2234711, rs1327474, polymorphism and TB susceptibility in different ethnicities.

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Cheng et al. 10.3389/fpubh.2022.976221

FIGURE 1
Flow diagram for identification of eligible studies for this meta-analysis.

All analyses were performed using STATA statistics software we further excluded 9 articles which did not meet the inclusion
(Version 12.0, Stata Corporation, College Station, Texas 77, 845 criteria. Finally, we included 14 articles with 15 case-control
United States). The statistical tests were all two-sided with a studies for the meta-analysis (17–30).
significance level of 0.05, unless otherwise specified.

Characteristics of included studies

Results
The general characteristics of each included study are
Literature search summarized in Table 1. In total, 15,988 participants were
included across all studies with 7,699 TB cases and 8,289
Figure 1 presents the study selection flow. A total of 387 controls. Eight articles (21–23, 26–30) were performed in Asians,
publications were retrieved from preliminary database search. four (17, 18, 20, 24) were performed in Africans, and two
Of these, 141 articles were removed as they were duplicates, (19, 25) were conducted in Europeans. Eleven (17–25, 27,
leaving 246 articles for further review. By reading titles and 28), eight (17, 19, 21, 22, 26, 27, 29, 30), and seven (17,
abstracts, 223 were excluded as they were not relevant to our 21, 23–25, 29, 30) studies reported the rs2234711, rs1327474,
study. Through reading the full text of the remaining 23 articles, and rs7749390 polymorphisms, respectively. For rs2234711,

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Cheng et al.
TABLE 1 Basic information of studies included in this analysis.

Study Country, Sample size Diagnosed method Genotyping Type Specimen SNPs HWE
ethnicity (case/control) method

Awomoyi et al. (17) Gambia, African 320/320 Sputum smear PCR-RFLP PTB Blood rs1327474, rs2234711, >0.05
rs7749390
Bulat-Kardum (18) Croatia, European 244/521 Sputum smear and Chest PCR TB Blood rs1327474, rs2234711 >0.05
x-ray
Cooke et al. (19) Gambia, Guinea 682/619 Sputum smear or culture PCR-ARMS PTB Blood rs2234711 <0.05
Bissau, and the
Republic of
Conakry, African
Hwang et al. (20) Korea, Asian 80/80 Sputum smear PCR-ARMS PTB Blood rs1327474, rs2234711 >0.05
He et al. (21) China, Asian 222/188 Sputum smear or culture; PCR PTB or EPTB Blood rs1327474, rs2234711, >0.05
and/or Chest x-ray rs7749390
Lü et al. (22) China, Asian 1,434/1,412 Sputum smear or culture; PCR PTB Blood rs2234711, rs7749390 >0.05
and/or Chest x-ray
04

Rudko et al. (24) Russians, European 238/265 NA PCR-RFLP Primary lung TB and Blood rs2234711, rs7749390 >0.05
severe secondary TB
Russians, European 331/279 NA PCR-RFLP Primary lung TB and Blood rs2234711, rs7749390 >0.05
severe secondary TB
Naderi et al. (23) Iran, Asian 173/163 Clinical symptoms, sputum PCR PTB Blood rs1327474, rs7749390 >0.05 (rs7749390),
smear and Chest x-ray <0.05 (rs1327474)
Shin et al. (25) Korean, Asian 673/592 Clinical symptom and culture PCR PTB Blood rs1327474, rs2234711 >0.05
Mayer (26) Ghana, African 1,999/2,589 Sputum smear and/or culture PCR-HRM PTB Blood rs2234711, rs7749390 >0.05
Shamsi et al. (27) Iran, Asian 100/100 Culture PCR-RFLP PTB Blood rs1327474 >0.05
He et al. (28) China, Asian 467/503 Clinical symptoms, sputum PCR PTB Blood rs1327474, rs7749390 >0.05
smear and Chest x-ray
Ali et al. (29) Sudan, African 100/50 Sputum smear PCR-RFLP PTB Sputum and blood rs2234711 <0.05

10.3389/fpubh.2022.976221
samples
Wu et al. (30) China, Asian 636/608 Clinical symptoms, sputum iMLDR TB Blood rs2234711 >0.05
smear and Chest x-ray
frontiersin.org

TB, tuberculosis; PTB, pulmonary tuberculosis; EPTB, extrapulmonary tuberculosis; PCR, polymerase chain reaction; PCR-RFLP, PCR-restriction fragment length polymorphism; PCR-ARMS, PCR-Amplification refractory mutation system; PCR-HRM,
PCR-high-resolution melt; iMLDR, improved multiplex ligation detection reaction.
Cheng et al. 10.3389/fpubh.2022.976221

FIGURE 2
Forest plot of association between IFNGR1 rs2234711 polymorphism and tuberculosis susceptibility (dominant model: CC + CT vs. TT).

the genotype distributions in the controls deviated from the Association of IFNGR1 rs1327474
HWE in two studies (18, 20); for rs1237474, the genotype polymorphism with TB susceptibility
distributions in the controls deviated from the HWE in one
study (30); the genotype distributions in the controls were Eight case-control studies (17, 19, 21, 22, 26, 27, 29,
consistent with the HWE for rs7749390. The average NOS 30) (2,279 cases and 2,467 controls) were included in the
score for included studies was 7.4 (standard deviation: 1.1) meta-analysis on the association between IFNGR1 rs1327474
(Supplemental Table 1). polymorphism and TB susceptibility. The association of
IFNGR1 rs1327474 polymorphism with TB susceptibility was
not detected in the dominant model (GG + AG vs. AA) (OR =
Association of IFNGR1 rs2234711 0.83, 95% CI: 0.65–1.05) (Figure 3), allele model (G vs. A) (OR
polymorphism with TB susceptibility = 0.81, 95% CI 0.61–1.08), recessive model (GG vs. AG + AA)
(OR = 1.02, 95% CI 0.73–1.43), heterozygote model (AG vs. AA)
Eleven studies with 12 case-control studies (17–25, 27, 28) (OR = 0.81, 95% CI 0.62–1.07), homozygote model (GG vs. AA)
(6,989 cases and 7,523 controls) were included in the meta- (OR = 0.92, 95% CI 0.52–1.63), and additive model (GG vs. GA
analysis on the association between the IFNGR1 rs2234711 vs. AA) (OR = 0.83, 95% CI 0.61–1.12) (Table 2).
polymorphism and TB susceptibility. The pooled ORs indicated
no significant association in dominant model (CC + CT vs. TT)
(OR = 1.06, 95% CI 0.90–1.24) (Figure 2), allele model (C vs.
T) (OR = 0.99, 95% CI 0.90–1.08), recessive model (CC vs. TT Association of IFNGR1 rs7749390
+ CT) (OR = 1.02, 95% CI 0.94–1.11), heterozygote model (CT polymorphism with TB susceptibility
vs. TT) (OR = 1.05, 95% CI 0.87–1.26), homozygote model (CC
vs. TT) (OR = 0.98, 95% CI 0.84–1.16), and additive model (CC Seven studies with eight case-control studies (17, 21, 23–
vs. CT vs. TT) (OR = 1.01, 95% CI 0.91–1.11). The association 25, 29, 30) (5,184 cases and 5,719 controls) were included in the
of the IFNGR1 rs2234711 polymorphism with TB susceptibility meta-analysis on the association between the IFNGR1 rs7749390
was significant in Africans (dominant model: OR = 1.24, 95% polymorphism and the TB susceptibility. The pooled ORs from
CI: 1.01–1.52) and Asians (homozygote model: OR = 0.82, 95% the studies indicated no significant association in the dominant
CI: 0.70–0.98), respectively (Table 2). model (TT + TC vs. CC) (OR = 1.02, 95% CI 0.81–1.27)

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TABLE 2 Results of association between IFNGR1 gene polymorphisms and TB susceptibility.

Polymorphisms Genetic models Subgroup n OR (95%CI) I2 (%) P for heterogeneity

rs1327474 Dominant model

Total 8 0.83 (0.65, 1.05) 47.8 0.063
Asian 6 0.78 (0.56, 1.09) 58.4 0.034
African 1 0.83 (0.44, 1.55) NA NA
European 1 1.01 (0.73, 1.40) NA NA
Allele model
Total 7 0.81 (0.61, 1.08) 66.2 0.007
Asian 5 0.74 (0.48, 1.15) 73.4 0.005
African 1 0.84 (0.46, 1.53) NA NA
European 1 1.03 (0.83, 1.28) NA NA
Recessive model
Total 7 1.02 (0.73, 1.43) 0 0.473
Asian 5 0.79 (0.34, 1.83) 22.9 0.266
African 1 0.97 (0.06, 15.60) NA NA
European 1 1.09 (0.74, 1.61) NA NA
Heterozygote model
Total 7 0.81 (0.62, 1.07) 42.9 0.105
Asian 5 0.76 (0.51, 1.14) 57 0.054
African 1 0.82 (0.44, 1.54) NA NA
European 1 0.98 (0.70, 1.38) NA NA
Homozygote model
Total 6 0.92 (0.52, 1.63) 24.8 0.248
Asian 4 0.72 (0.23, 2.31) 51.9 0.1
African 1 0.95 (0.06, 15.18) NA NA
European 1 1.08 (0.69, 1.69) NA NA
Additive model
Total 6 0.83 (0.61, 1.12) 68.5 0.007
Asian 4 0.76 (0.47, 1.22) 77.1 0.004
African 1 0.85 (0.47, 1.53) NA NA
European 1 1.03 (0.83, 1.28) NA NA
rs2234711 Dominant model
Total 11 1.06 (0.90, 1.24) 64.4 0.002
Asian 5 0.96 (0.75, 1.23) 77 0.002
African 3 1.24 (1.01, 1.52) 0 0.395
European 3 1.13 (0.83, 1.54) 53.8 0.115
Allele model
Total 11 0.99 (0.90, 1.08) 59.7 0.006
Asian 4 0.89 (0.79, 0.99) 31 0.226
African 4 1.03 (0.87, 1.23) 66.8 0.029
European 3 1.06 (0.89, 1.26) 27.3 0.253
Recessive model
Total 11 1.02 (0.94, 1.11) 0 0.53
Asian 5 0.99 (0.86, 1.13) 35.4 0.185
African 3 1.10 (0.89, 1.36) 0 0.868
European 3 1.00 (0.76, 1.31) 0 0.37

(Continued)

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TABLE 2 (Continued)

Polymorphisms Genetic models Subgroup n OR (95%CI) I2 (%) P for heterogeneity

Heterozygote model
Total 10 1.05 (0.87, 1.26) 58.2 0.011
Asian 4 0.88 (0.71, 1.10) 35.6 0.198
African 3 1.24 (1.00, 1.54) 0 0.447
European 3 1.15 (0.79, 1.65) 62.9 0.068
Homozygote model
Total 10 0.98 (0.84, 1.16) 25.6 0.208
Asian 4 0.82 (0.70, 0.98) 0 0.556
African 3 1.26 (0.98, 1.62) 0 0.549
European 3 1.04 (0.7, 1.40) 0 0.607
Additive model
Total 10 1.01 (0.92, 1.11) 45 0.06
Asian 4 0.90 (0.83, 0.97) 0 0.511
African 3 1.13 (0.99, 1.28) 0 0.489
European 3 1.06 (0.89, 1.25) 23.2 0.272
rs7749390 Dominant model
Total 7 1.02 (0.81, 1.27) 61.9 0.015
Asian 4 1.00 (0.71, 1.41) 78.1 0.003
African 1 0.96 (0.65, 1.42) NA NA
European 2 1.15 (0.79, 1.67) 0 0.361
Allele model
Total 8 0.98 (0.88, 1.09) 58.5 0.018
Asian 4 1.07 (0.88, 1.29) 72.4 0.012
African 2 0.89 (0.82, 0.98) 0 0.481
European 2 0.89 (0.66, 1.20) 55.8 0.132
Recessive model
Total 7 1.02 (0.85, 1.23) 47.2 0.078
Asian 4 1.16 (0.92, 1.47) 47.9 0.124
African 1 0.99 (0.68, 1.45) NA NA
European 2 0.77 (0.57, 1.05) 19.5 0.265
Heterozygote model
Total 7 1.00 (0.78, 1.27) 62.5 0.014
Asian 4 0.93 (0.66, 1.31) 76.1 0.006
African 1 0.96 (0.63, 1.47) NA NA
European 2 1.30 (0.88, 1.27) 0 0.64
Homozygote model
Total 7 1.05 (0.83, 1.34) 50.8 0.058
Asian 4 1.14 (0.77, 1.69) 73.2 0.011
African 1 0.97 (0.60, 1.56) NA NA
European 2 0.97 (0.64, 1.46) 0 0.324
Additive model
Total 7 1.03 (0.90, 1.19) 64.5 0.01
Asian 4 1.07 (0.87, 1.30) 75.1 0.007
African 1 1.21 (0.92, 1.60) NA NA
European 2 0.89 (0.67, 1.19) 52.9 0.145

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FIGURE 3
Forest plot of association between IFNGR1 rs1327474 polymorphism and tuberculosis susceptibility (dominant model: GG + AG vs. AA).

(Figure 4), allele model (T vs. C) (OR = 0.98, 95% CI 0.88– did not alter markedly in each model, except that rs1327474
1.09), recessive model (TT vs. CC + TC) (OR = 1.02, 95% CI seemed to be a protective polymorphism for TB risk in dominant
0.85–1.23), heterozygote model (TC vs. CC) (OR = 1.00, 95% model (OR = 0.77, 95% CI: 0.60–0.99).
CI 0.78–1.27), homozygote model (TT vs. CC) (OR = 1.05, 95%
CI 0.83–1.34), and additive model (TT vs. TC vs CC) (OR =
1.03, 95% CI 0.90–1.19). However, the association between the Publication bias
IFNGR1 rs7749390 polymorphism and TB susceptibility in the
allele model was significant in Africans (OR = 0.89, 95% CI: The Begg’s test and Egger’s test were used to evaluate the
0.82–0.98) (Table 2). publication bias of the included studies in this meta-analysis.
The shape of Begg’s funnel plot revealed no evidence of obvious
asymmetry in all genetic models, which showed no potential
Sensitivity analysis publication bias (Supplementary Figures 1–3). Meanwhile, the
statistical results from Egger’s test and Begg’s test also indicating
In the sensitivity analysis of the results from the dominant that there was no publication bias across studies (all p > 0.05).
models, the influence of each individual data set on the pooled
OR was assessed by removing each study individually. When
excluding the results from Lu et al.’s (23) study, the pooled Discussion
OR (1.13, 95% CI: 1.02–1.26) indicated an association between
rs2234711 and TB susceptibility. When excluding the result To our knowledge, this is the first meta-analysis that
from Naderi et al.’s study (30), rs1327474 was suggested to have systematically assessed the association of the IFNGR1
a protective effect on TB susceptibility (OR = 0.77, 95% CI: rs2234711, rs1327474, and rs7749390 polymorphisms with
0.60, 0.99). For rs7749390, the sensitivity analysis demonstrated TB susceptibility. Based on 14 case-control studies with 15,988
relatively robust results with an OR range from 0.95(95% CI: participants, we found that IFNGR1 gene polymorphism was
0.76, 1.18) when excluding He et al.’s (21) study to 1.10 (95% associated with TB susceptibility in some ethnic groups.
CI: 0.89, 1.37) when omitting Lu et al’s. (23) study. Various gene polymorphisms in the IFNGR1 are suggested
To assess the possible effects of studies in which SNPs were to be associated with susceptibility of diverse diseases,
not in HWE, we conducted a sensitivity analysis by omitting such as inflammatory and virus-associated disorders (36–
these studies and re-pooled the results. However, the overall ORs 38). For the association of IFNGR1 gene polymorphisms

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FIGURE 4
Forest plot of association between IFNGR1 rs7749390 polymorphism and tuberculosis susceptibility (dominant model: TT + TC vs. CC).

with TB susceptibility, Wang et al. (39) conducted a meta- among Africans in our study, which indicated that the
analysis focused on IFNGR1 rs2234711 polymorphism. T allele was associated with decreased risk for TB in the
Based on a total of six studies comprising 1,497 confirmed African population. The rs1327474 polymorphism, which is
TB cases and 1,802 controls, Wang et al. (39) observed located in the promoter region of the IFNGR1 gene, has been
no significant association between IFNGR1 rs2234711 shown to have higher transcriptional activity (21). He et al.
polymorphism and TB susceptibility. However, like the reported that the rs1327474 variant was associated with a
present meta-analysis, the association between IFNGR1 decreased risk of pulmonary TB (21). In this meta-analysis,
rs2234711 polymorphism and TB susceptibility was also however, similar association was only found in Africans
found in Africans (dominant model: CC + TC vs. TT, OR (dominant model).
= 1.24, 95% CI 1.02–1.51) in Wang et al.’s meta-analysis. Gene polymorphisms are complicated and fluctuating,
Nevertheless, the results from the present meta-analysis were especially among different ethnicities and populations from
more reliable because of more included studies and larger different regions (41–43). Studies have revealed that discrepancy
sample size. in distribution of IFNGR1 genotype may exist in different
The rs2234711 polymorphism is located within the populations (44), which may contribute to the inconsistent
AP4 binding site in the 5’ upstream region of the gene. associations of genetic polymorphisms with TB susceptibility.
This region has been associated with susceptibility to some The minor allele frequency of the SNP s2234711 varies
infectious diseases, including TB (36, 37, 40). In this meta- greatly in different areas, ranging from 0% in European
analysis, significant association of rs2234711 polymorphism populations to 60% in African–American populations (23).
with TB susceptibility was detected in Africans (dominant Furthermore, studies have shown that the genetic variation of
model) and in Asians (homozygote model, allele model, the bacteria and the phylogeographic distribution of the TB-
and additive model). The result indicated that the c allele causing bacteria differed from ethnicity or populations, and
might be a potential risk factor for TB infection in Africans, patients of different ethnicity presents different TB phenotypes
whereas providing a protective effect against TB infection (45). Moreover, the burden of TB is much higher in Asia
in Asians. Therefore, rs2234711 polymorphism may exert and Africa geographically than that in other regions (46–48).
inversed effect on Africans and Asians. The rs7749390 There is a necessity to further explore the possible effects
polymorphism is located in an exon/intron splice site of IFNGR1 gene polymorphisms on TB risk among more
and likely to influence the intron–exon splicing process. specifically defined ethnicities, such as the Caucasians, Africans,
Significant association were detected in the allele model and Mongolians.

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Cheng et al. 10.3389/fpubh.2022.976221

This meta-analysis indicated that Africans and Asians warranted to confirm the present findings among different
seem to be more sensitive to IFNGR1 gene polymorphisms ethnic groups.
compared with other ethnicities. It might be partially explained
by the several factors. First, most of the original studies
on TB were conducted in Asian and African populations, Data availability statement
which provides more statistical power for detecting significant
results. Second, the prevalence of TB was relatively high The original contributions presented in the study are
among Asians or Africans within the studies assessed here included in the article/Supplementary material, further inquiries
(49, 50), therefore more gene mutations could be detected. can be directed to the corresponding authors.
Third, environmental factors, such as diet, rainfall capacity,
and social-economic factors in Asians or Africans may facilitate
TB infection.
Author contributions
The present study systematically assessed the association
XY and JC conceived and designed the experiments. LC, FZ,
between IFNGR1 gene polymorphisms and TB susceptibility.
and YW performed the experiments. LC, JC, and FZ analyzed
Strength of this meta-analysis was that the overall results
the data. LC, XY, and YW contributed reagents, materials,
were generally robust, as suggested by the subgroup analysis
and analysis tools. LC and FZ wrote the paper. All authors
and sensitivity analysis. Nevertheless, some limitations
reviewed the manuscript. All authors contributed to the article
should be noted. First, all included studies were case-control
and approved the submitted version.
studies. Some included studies used matched controls (e.g.,
age and sex matched), while others did not. Confounding
factors, such as, age, sex, HIV status, and TB severity,
were not adjusted, which may lead to underestimation or
Conflict of interest
overestimation of the risk estimates. Second, the number
The authors declare that the research was conducted in the
of included studies were relatively limited, and there was
absence of any commercial or financial relationships that could
significant heterogeneity across studies, the geographic region,
be construed as a potential conflict of interest.
characteristics of participants, diagnosed method, genotyping
method may all contribute to the heterogeneity across studies,
the strength of our findings may be weakened. Third, this Publisher’s note
meta-analysis included studies (18, 20, 30) in which the SNPs
were not in HWE, stability of the results could be affected, All claims expressed in this article are solely those of the
although sensitivity analysis omitting these studies (18, 20, 30) authors and do not necessarily represent those of their affiliated
showed that the re-pooled ORs were consistent with the organizations, or those of the publisher, the editors and the
overall ORs. reviewers. Any product that may be evaluated in this article, or
In conclusion, this meta-analysis indicated that claim that may be made by its manufacturer, is not guaranteed
IFNGR1 rs2234711 polymorphism was associated with or endorsed by the publisher.
increased TB susceptibility in Africans and decreased
TB susceptibility in Asians, while IFNGR1 rs7749390
polymorphism was associated with decreased TB susceptibility Supplementary material
in Africans. This study provided evidence that IFNGR1
rs2234711 might be involved in the pathogenesis of The Supplementary Material for this article can be found
TB in certain ethnic groups. However, further studies online at: https://www.frontiersin.org/articles/10.3389/fpubh.
with larger sample size and more stringent design are 2022.976221/full#supplementary-material

References
1. Glaziou P, Floyd K, Raviglione MC. Global epidemiology of tuberculosis. 3. Furin J, Cox H, Pai M. Tuberculosis. Lancet. (2019) 393:1642–
Semin Respir Crit Care Med. (2018) 39:271–85. doi: 10.1055/s-0038-1651492 56. doi: 10.1016/S0140-6736(19)30308-3
2. World Health Organization. Global Tuberculosis Report 2019. Available online 4. Lange C, Dheda K, Chesov D, Mandalakas AM, Udwadia Z, Horsburgh
at: https://www.who.int/tb/publications/global_report/en/ (2019). (accessed May CR. Management of drug-resistant tuberculosis. Lancet. (2019) 394:953–
23, 2022). 66. doi: 10.1016/S0140-6736(19)31882-3

Frontiers in Public Health 10 frontiersin.org

Cheng et al. 10.3389/fpubh.2022.976221

5. Bellamy R. Susceptibility to mycobacterial infections: the importance of host 25. Shin JG, Park BL, Kim LH, Namgoong S, Kim JO, Chang HS, et al. Association
genetics. Genes Immun. (2003) 4:4–11. doi: 10.1038/sj.gene.6363915 study of polymorphisms in interferon-γ receptor genes with the risk of pulmonary
tuberculosis. Mol Med Rep. (2015) 12:1568–78. doi: 10.3892/mmr.2015.3544
6. Li C, Zhan Y, Li GZ, Liu SG. Association between severe preeclampsia
and single nucleotide polymorphism of macrophage migration inhibitory 26. Meyer CG, Intemann CD, Förster B, Owusu-Dabo E, Franke A, Horstmann
factors−173G/C. Zhonghua Fu Chan Ke Za Zhi. (2012) 47:342–6. RD, et al. No significant impact of IFN-γ pathway gene variants on tuberculosis
doi: 10.3760/cma.j.issn.0529-567x.2012.05.006 susceptibility in a West African population. Eur J Hum Genet. (2016) 24:748–
55. doi: 10.1038/ejhg.2015.172
7. Guo YL, Liu Y, Ban WJ, Sun Q, Shi GL. Association of mannose-binding lectin
gene polymorphisms with the development of pulmonary tuberculosis in China. 27. Shamsi M, Zolfaghari MR, Farnia P. Association of IFN-γ and P2X7
BMC Infect Dis. (2017) 17:210. doi: 10.1186/s12879-017-2310-3 receptor gene polymorphisms in susceptibility to tuberculosis among iranian
patients. Acta Microbiol Immunol. (2016) 63:93–101. doi: 10.1556/030.63.20
8. Dou HY, Chen YY, Kou SC, Su IJ. Prevalence of mycobacterium tuberculosis
16.1.7
strain genotypes in Taiwan reveals a close link to ethnic and population migration.
J Formos Med Assoc J. (2015) 114:484–8. doi: 10.1016/j.jfma.2014.07.006 28. He S, Wang B, Zhu X, Chen Z, Chen J, Hua D, et al. Association
of IFNGR1 and IFNG genetic polymorphisms with the risk for pulmonary
9. Cavalcanti YV, Brelaz MC, Neves JK, Ferraz JC, Pereira VR. Role of TNF-
tuberculosis in the Chinese Tibetan population. Oncotarget. (2017) 8:98417–
Alpha, IFN-Gamma, and IL-10 in the development of pulmonary tuberculosis.
25. doi: 10.18632/oncotarget.21413
Pulm Med. (2012) 2012:745483. doi: 10.1155/2012/745483
29. Ali AH, Omer AA, Saeed NS, Mansour EE, Elhassan MM. Influence
10. Merlin G, van der Leede BJ, McKune K, Knezevic N, Bannwarth W, Romquin
of interferon-gamma Receptor 1 gene polymorphisms on the susceptibility to
N, et al. The gene for the ligand binding chain of the human interferon gamma
pulmonary tuberculosis among sudanese population. Int J Mycobacteriol. (2018)
receptor. Immunogenetics. (1997) 45:413–21. doi: 10.1007/s002510050223
7:26–31. doi: 10.4103/ijmy.ijmy_206_17
11. Dupuis S, Döffinger R, Picard C, Fieschi C, Altare F, Jouanguy E, et al. Human
30. Wu S, Wang Y, Zhang M, Wang M, He JQ. Genetic variants
interferon-gamma-mediated immunity is a genetically controlled continuous trait
in IFNG and IFNGR1 and tuberculosis susceptibility. Cytokine. (2019)
that determines the outcome of mycobacterial invasion. Immunol Rev. (2000)
123:154775. doi: 10.1016/j.cyto.2019.154775
178:129–37. doi: 10.1034/j.1600-065X.2000.17810.x
31. Wells GA SB, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P. The
12. Johnson HM, Noon-Song E, Ahmed CM. Controlling nuclear
Newcastle-Ottawa Scale (NOS) for Assessing the Quality if Nonrandomized Studies
jaks and stats for specific gene activation by ifn γ and other cytokines:
in Meta-Analyses, 2012. Available online at: https://www.ohri.ca//programs/
a possible steroid-like connection. J Clin Cell Immunol. (2011)
clinical_epidemiology/oxford.asp (accessed May 28, 2022).
2:1000112. doi: 10.4172/2155-9899.1000113
32. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat
13. Jouanguy E, Lamhamedi-Cherradi S, Altare F, Fondanèche MC, Tuerlinckx
Med. (2002) 21:1539–58. doi: 10.1002/sim.1186
D, Blanche S, et al. Partial interferon-gamma receptor 1 deficiency in a child
with tuberculoid bacillus Calmette-Guérin infection and a sibling with clinical 33. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in
tuberculosis. J Clin Investig. (1997) 100:2658–64. doi: 10.1172/JCI119810 meta-analyses. BMJ. (2003) 327:557–60. doi: 10.1136/bmj.327.7414.557
14. Altare F, Jouanguy E, Lamhamedi-Cherradi S, Fondanéche MC, Fizame C, 34. Begg CB, Mazumdar M. Operating characteristics of a rank correlation
Ribiérre F, et al. A causative relationship between mutant IFNgR1 alleles and test for publication bias. Biometrics. (1994) 50:1088–101. doi: 10.2307/25
impaired cellular response to IFNgamma in a compound heterozygous child. Am J 33446
Hum Genet. (1998) 62:723–6. doi: 10.1086/301750
35. Egger M, Davey Smith G, Schneider M, Minder C. Bias in
15. Ryberg A, Petersson F, Redeen S, Eriksson O, Borch K. Host gene meta-analysis detected by a simple, graphical test. BMJ. (1997)
polymorphisms in relation to helicobacter pylori infection and associated 315:629–34. doi: 10.1136/bmj.315.7109.629
diseases in a population based cohort. Gastroenterol Res. (2013) 6:207–
36. Koch O, Awomoyi A, Usen S, Jallow M, Richardson A, Hull J, et al. IFNGR1
18. doi: 10.4021/gr578w
gene promoter polymorphisms and susceptibility to cerebral malaria. J Infect Dis.
16. Zhuo Y, Yang Y, Zhang M, Xu Y, Chen Z, Mu L, et al. Single nucleotide (2002) 185:1684–7. doi: 10.1086/340516
polymorphisms in IFN-γ signaling pathway associated with risk of hepatitis B
37. Thye T, Burchard GD, Nilius M, Müller-Myhsok B, Horstmann RD.
virus infection in Chinese children. Can J Infect Dis Med Microbiol. (2020)
Genomewide linkage analysis identifies polymorphism in the human interferon-
2020:8121659. doi: 10.1155/2020/8121659
gamma receptor affecting Helicobacter pylori infection. Am J Hum Gemet. (2003)
17. Awomoyi AA, Nejentsev S, Richardson A, Hull J, Koch O, Podinovskaia M, 72:448–53. doi: 10.1086/367714
et al. No association between interferon-gamma receptor-1 gene polymorphism
38. Canedo P, Corso G, Pereira F, Lunet N, Suriano G, Figueiredo C, et al.
and pulmonary tuberculosis in a Gambian population sample. Thorax. (2004)
The interferon gamma receptor 1 (IFNGR1)−56C/T gene polymorphism is
59:291–4. doi: 10.1136/thx.2003.013029
associated with increased risk of early gastric carcinoma. Gut. (2008) 57:1504–
18. Bulat-Kardum L, Etokebe GE, Knezevic J, Balen S, Matakovic-Mileusnic N, 8. doi: 10.1136/gut.2007.143578
Zaputovic L, et al. Interferon-gamma receptor-1 gene promoter polymorphisms
39. Wang W, Ren W, Zhang X, Liu Y, Li C. Association between interferon
(G-611A; T-56C) and susceptibility to tuberculosis. Scand J Immunol. (2006)
gamma receptor 1-56C/T gene polymorphism and tuberculosis susceptibility: a
63:142–50. doi: 10.1111/j.1365-3083.2005.01694.x
meta-analysis. Chin Med J. (2014) 127:3782–8.
19. Cooke GS, Campbell SJ, Sillah J, Gustafson P, Bah B, Sirugo G,
40. Martínez-Morales MC, Deswarte C, Castañeda-Casimiro J, Bustamante
et al. Polymorphism within the interferon-gamma/receptor complex
J, Blancas-Galicia L, Scheffler-Mendoza S. Disseminated infection by
is associated with pulmonary tuberculosis. Am J Respir Crit. (2006)
M. tuberculosis complex in patient with IFN-γ receptor 1 complete
174:339–43. doi: 10.1164/rccm.200601-088OC
deficiency. Rev Alerg Mex. (2017) 64:499–504. doi: 10.29262/ram.v64
20. Hwang JH, Kim EJ, Kim SY, Lee SH, Suh GY, Kwon OJ, et al. i4.329
Polymorphisms of interferon-gamma and interferon-gamma receptor
41. Gelernter J, Kranzler H, Coccaro EF, Siever LJ, New AS. Serotonin
1 genes and pulmonary tuberculosis in Koreans. Respirology. (2007)
transporter protein gene polymorphism and personality measures in African
12:906–10. doi: 10.1111/j.1440-1843.2007.01171.x
American and European American subjects. Am J Psychiatr. (1998) 155:1332–
21. He J, Wang J, Lei D, Ding S. Analysis of functional SNP in ifng/ifngr1 8. doi: 10.1176/ajp.155.10.1332
in Chinese Han population with tuberculosis. Scand J Immunol. (2010) 71:452–
42. Govan VA, Constant D, Hoffman M, Williamson AL. The
8. doi: 10.1111/j.1365-3083.2010.02393.x
allelic distribution of−308 Tumor Necrosis Factor-alpha gene
22. Lü J, Pan H, Chen Y, Tang S, Feng Y, Qiu S, et al. Genetic polymorphisms of polymorphism in South African women with cervical cancer and
IFNG and IFNGR1 in association with the risk of pulmonary tuberculosis. Gene. control women. BMC Cancer. (2006) 6:24. doi: 10.1186/1471-24
(2014) 543:140–4. doi: 10.1016/j.gene.2014.03.042 07-6-24
23. Naderi M, Hashemi M, Rezaei M, Safdari A. Association of genetic 43. Rizzo SR, Gazito D, Pott-Junior H, Latini FR, Castelo A. Prevalence
polymorphisms of IFNGR1 with the risk of pulmonary tuberculosis in Zahedan, of IFNL3 gene polymorphism among blood donors and its relation to
Southeast Iran. Tuber Res Treat. (2015) 2015:292505. doi: 10.1155/2015/292505 genomic profile of ancestry in Brazil. Braz J Infect Dis. (2016) 20:619–
22. doi: 10.1016/j.bjid.2016.10.002
24. Rudko AA, Garaeva AF, Bragina EY, Babushkina NP, Kolokolova
OV, Lipaenkova ON, et al. Mutations in genes underlying atypical 44. Rosenzweig SD, Schäffer AA, Ding L, Sullivan R, Enyedi B, Yim
familial mycobacteriosis are not found in tuberculosis patients from JJ, et al. Interferon-gamma receptor 1 promoter polymorphisms: population
Siberian populations. Tuberculosis (Edinburgh, Scotland). (2015) distribution and functional implications. Clin Immunol. (2004) 112:113–
95:204–7. doi: 10.1016/j.tube.2015.01.002 9. doi: 10.1016/j.clim.2004.03.018

Frontiers in Public Health 11 frontiersin.org

Cheng et al. 10.3389/fpubh.2022.976221

45. Jagielski T, Minias A, van Ingen J, Rastogi N, Brzostek income countries: a systematic review and meta-analysis. PLoS Med. (2016)
A, Zaczek A, et al. Methodological and clinical aspects of the 13:e1002119. doi: 10.1371/journal.pmed.1002119
molecular epidemiology of mycobacterium tuberculosis and other
48. Houben RM, Dodd PJ. The global burden of latent tuberculosis
mycobacteria. Clin Microbiol Rev. (2016) 29:239–90. doi: 10.1128/CMR.00
infection: a re-estimation using mathematical modelling. PLoS Med. (2016)
055-15
13:e1002152. doi: 10.1371/journal.pmed.1002152
46. Zielonka TM. Epidemiological situation of tuberculosis in the world based 49. Bishwajit G, Ide S, Ghosh S. Social determinants of infectious diseases in
on a report of the World Health Organization 2013. Przegl Epidemiol. (2015) South Asia. Int Sch Res Notices. (2014) 2014:135243. doi: 10.1155/2014/135243
69:687–91, 837-40.
50. Warren R, Ismail N, Chegou NN, Theron G, Walzl G, Malherbe ST, et al.
47. Horton KC, MacPherson P, Houben RM, White RG, Corbett EL. Sex Tuberculosis research in South Africa over the past 30 years: From bench to
differences in tuberculosis burden and notifications in low- and middle- bedside. S Afr Med J. (2019) 109:45–52. doi: 10.7196/SAMJ.2019.v109i11b.14249

Frontiers in Public Health 12 frontiersin.org