Association between IL-10 Gene Polymorphisms and Susceptibility of Tuberculosis: Evidence Based on a Meta-Analysis
Kong H (2014) Association between IL-10 Gene Polymorphisms and Susceptibility of Tuberculosis: Evidence Based on a Meta-
Analysis. PLoS ONE 9(2): e88448. doi:10.1371/journal.pone.0088448
Association between IL-10 Gene Polymorphisms and Susceptibility of Tuberculosis: Evidence Based on a Meta-Analysis
Bin Liang 0
Yang Guo 0
Yunhui Li 0
Hong Kong 0
0 1 Department of Clinical Laboratory, High Vocational Technological College, China Medical University , Shenyang , China , 2 Department of Breast Surgery, General Surgery, The First Hospital of China Medical University , Shenyang , China , 3 Department of Clinical Laboratory, No.202 Hospital , Shenyang , China , 4 Department of Clinical Laboratory, Shengjing Hospital, China Medical University , Shenyang , China
Background: A number of observational studies have been conducted to investigate the association of IL-10 gene polymorphisms with tuberculosis (TB) susceptibility. However, the results of different studies were inconsistent. The aim of this study was to investigate the relationship between IL-10 -1082G/A, -819T/C, and -592A/C polymorphisms and TB risk by meta-analysis. Methods: A literature search was conducted among six English databases (PubMed, Embase, Web of Science, Science Direct, SpringerLink and EBSCO) and two Chinese databases (Wanfang and Chinese National Knowledge Infrastructure databases) to identify studies involving association between IL-10 21082G/A, 2819T/C, and 2592A/C polymorphisms and TB susceptibility before May. 2013. Statistical analysis was performed using Revman 5.0 and Stata 12.0. Results: A total of 31 studies with 6,559 cases and 7,768 controls were included in this meta-analysis. The results showed that three polymorphisms (-1082G/A, -819T/C, and -592A/C) in the IL-10 gene were not associated with the risk of TB in general population. In the subgroup analysis by ethnicity, IL-10 -1082G/A polymorphism was associated with TB risk in Europeans (AA+AG vs. GG: OR = 0.57, 95% CI = 0. 0.37-0.89, P = 0.01) and Americans (AA+AG vs. GG: OR = 0.39, 95% CI = 0.27-0.57, P,0.01), and IL-10 -819T/C (C allele vs. T allele: OR = 0.83, 95% CI = 0.72-0.96, P = 0.01) and -592A/C (CC+AC vs. AA: OR = 0.65, 95% CI = 0.49-0.85, P = 0.002) polymorphisms were significantly associated with TB risk in Asians. Conclusion: This meta-analysis provides strong evidence that IL-10-1082G/A polymorphism was associated with TB risk in Europeans and Americans, and IL-10 -819T/C and -592A/C polymorphisms could be risk factors for TB in Asians. Additional well designed large studies were required for the validation of our results.
Funding: This study was supported by Liaoning Natural Science Fund, Liaoning Province, China (Topic No: 201102257). The funders had no role in study design,
data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Tuberculosis (TB) is a chronic infectious disease that occurs
worldwide, leading to 1.6 million deaths annually worldwide .
However, from the estimated 2 billion individuals that have been
initially infected with Mycobacterium tuberculosis (M. tuberculosis), only
5% to 10% develop symptomatic TB . The exact reasons as to
why only some of the individuals exposed to M. tuberculosis develop
uncontrolled disease and others have an effective immune
response to limit the spread of the pathogen remains unknown.
The genetic influence on TB infection was established by several
studies of monozygotic and dizygotic twins, linkage and candidate
gene analysis, indicating that genetics may play a role in the
susceptibility to TB infection .
A major determinant for the clinical expression of the different
forms of TB, and their final outcome, is the interaction between
the pathogen and the host immune system. Cytokines play an
important role in anti-TB immune response, and cytokines
interleukin -10 (IL-10) have been implicated in the pathogenesis
of TB . IL-10 is an important immunoregulatory cytokine
mainly produced by macrophages, monocytes, T cells, B cells,
dendritic cells, mast cells and eosinophils . Turner J, et al.
demonstrated that increased susceptibility to reactivation
tuberculosis in the mouse model is strongly influenced by the expression
of IL-10 during the chronic or latent phase of the infection .
IL10 potentially helps M. tuberculosis persistence in humans by
blocking phagosome maturation in macrophages . The ability
of IL-10 to down-regulate immune responses and the fact that
IL10 can be detected in tuberculosis patients have led researchers to
investigate whether IL-10 plays a role in susceptibility to
Figure 1. Flow diagram of the literature search and trial selection process.
Certain single nucleotide polymorphisms within the promoter
region of the IL-10 gene have been associated with altered levels of
circulating IL-10, such as 21082G/A, 2819T/C, and 2592A/C
[12,13]. These polymorphisms have been investigated as potential
susceptibility factors for TB. Given the functional significance of
this genetic variant, a number of case-control studies have been
done in different populations to investigate its susceptibility
towards TB, but the findings remain conflicting rather than
conclusive. Therefore, we conducted a systematic review and
meta-analysis to get a more precise estimate of the association
between IL-10 polymorphisms and TB risk.
Materials and Methods
Literature Search Strategy
A literature search was conducted among six English databases
(PubMed, Embase, Web of Science, Science Direct, SpringerLink
and EBSCO) and two Chinese databases (Wanfang and Chinese
National Knowledge Infrastructure databases) to identify studies
involving association between IL-10 21082G/A, 2819T/C, and
2592A/C polymorphisms and TB susceptibility before May.
2013. Key words used in the research included interleukin,
interleukin-10, cytokine, tuberculosis, Mycobacterium
tuberculosis, single nucleotide polymorphism, variant, genotype,
mutation. To minimize potential publication bias, no
restrictions were placed on language, sample size, and time period.
Inclusion and Exclusion Criteria
All included studies have to fulfill the following characteristics
and inclusion criteria: (a) case-control studies focused on
associations between IL-10 -1082G/A, -819T/C, and 2592A/C
polymorphisms and the risk of TB; (b) the diagnosis of TB should
meet the internationally accepted criteria; (c) genotype distribution
in both cases and controls were available for estimating an odds
ratio (OR) with 95% confidence interval (CI). The exclusion
criteria of the meta-analysis were: (a) animal studies; (b)
metaanalyses, letters, reviews, meeting abstracts, or editorial comments;
(c) studies with duplicate data, incomplete data, and unavailable
data. When an individual author published several articles
obtained from the same patient population, only the newest or
most complete article was included in the analysis.
Data were independently abstracted by two reviewers (Liang
and Li) using a standard protocol and data-collection according to
the inclusion criteria. The following data were collected from each
study: first authors name, year of publication, country, ethnicity,
source of controls, sample size, genotyping method, and number of
cases and controls for IL-10 21082G/A, 2819T/C, and 2592A/
C polymorphisms. An attempt was made to contact authors if data
presentation was incomplete or if it was necessary to resolve an
apparent conflict or inconsistency in the article. Any
disagreements were resolved by consensus.
Review manager 5.0 program provided by the Cochrane
Library and Stata (Version12.0, Stata Corporation) were used to
perform all the statistical analysis. The combined odds ratio (OR)
Sample size SNP studied
0.379, 0.125, 0.125
0.060, 0.320, 0.320
0.020, 0.957, 0.957
0.674, 0.410, 0.518
0.524, 0.062, 0.035
,0.001, 0.671, 0.671
PB, population-based controls, HB, hospital-based controls. HWE, HardyWeinberg equilibrium. PCR, polymerase chain reaction; SSP, sequence-specific primers; ARMS,
amplification refractory mutation system; RFLP, restriction fragment length polymorphism; FRET, fluorescence resonance energy transfer. MAPA, multiplex automated
primer extension analysis.
with its 95% confident interval (CI) was used to assess the strength
of the association between the IL-10 polymorphisms and TB risk.
The significance of the combined OR was determined by the
Ztest, in which P,0.05 was considered significant. The pooled ORs
were calculated for allele model (mutation [M] allele versus wild
[W] allele), dominant model (WM+MM versus WW), recessive
model (MM versus WM+WW), homozygote comparison (MM
versus WW), and heterozygote comparison (WM versus WW),
respectively. Two models of pooling data for dichotomous
outcomes were conducted: the random-effects model and the
fixed-effects model. Heterogeneity assumption was assessed by the
Chisquare based Q test and was regarded to be statistically
significant if P,0.10. When the P$0.10, the pooled statistical
analysis was calculated by the fixed-effects model, otherwise, a
random-effect model was used. To evaluate the ethnicity-specific
effects, subgroup analyses were performed by ethnic group. The
,0.01 0.53 [0.201.41]
OR [95% CI]
AA vs. GG+GA
CC vs. TC+TT
CC vs. AC+AA
OR [95% CI]
OR [95% CI]
A allele vs. G allele
OR [95% CI]
C allele vs. T allele
C allele vs. A allele
OR [95% CI]
AA+GA vs. GG
CC+TC vs. TT
CC+AC vs. AA
,0.01 0.65 [0.490.85]
,0.01 0.49 [0.340.71]
,0.01 0.70 [0.550.89]
potential publication bias was assessed by Beggs funnel plot and
Eggers test [14,15].
Characteristics of Studies
The flow chart that displays the study selection process was
shown in Figure 1. A total of 31 case-control studies, including
6,559 cases and 7,768 controls, were finally identified according to
inclusion and exclusion criteria. There are 29 case-control studies
concerning -1082G/A polymorphism , 14 case-control
studies concerning -819T/C polymorphism [16,18,20
23,25,31,33,3739,42,45], and 16 case-control studies concerning
-592A/C polymorphism [16,2025,28,31,33,3740,45,46].
Among the 31 eligible studies, 17 of them were of Asians
[16,18,19,26,28,3032,34,36,39,4144,46], 6 studies were of
Europeans [17,21,25,27,35,37], 5 studies were of Africans
[20,22,29,33,38], and 3 studies were of Americans [23,24,40].
Controls were selected from healthy population in all studies and
most studies used frequency-matched controls to the cases by age,
sex, or ethnicity. The genotype distributions among the controls of
all studies were in agreement with HWE except for ten studies for
the -1082G/A, two studies for the -819T/C, and three studies for
the -592A/C. The detailed characteristics of the eligible studies
included in this meta-analysis were shown in Table 1.
Quantitative Data Synthesis
The evaluation of association between IL-10 polymorphisms
and TB risk was presented in Table 2.
Of the 31 studies investigating the association between IL-10
1082G/A polymorphism and TB susceptibility, 29 provided
enough data to calculate ORs, including 6,199 cases and 7,406
controls. The results of pooling all studies showed that the IL10
1082 G/A polymorphism was not associated with TB
susceptibility in general population under all genetic models (A allele vs. G
allele: OR = 0.97, 95% CI = 0.791.20, P = 0.81; AA+GA vs. GG:
OR = 0.95, 95% CI = 0.681.34, P = 0.79; AA vs. GA+ GG:
OR = 0.92, 95% CI = 0.751.14, P = 0.46; AA vs. GG: OR =
0.90, 95% CI = 0.611.33, P = 0.59; GA vs. GG: OR = 0.99, 95%
CI = 0.721.36, P = 0.96) (Figure 2). In the stratified analysis by
ethnicity, we found that TB risk was significant decreased in
European group under dominant model (Figure 2) (AA+GA vs.
GG: OR = 0.57, 95% CI = 0.370.89, P = 0.01) and
heterozygous model (GA vs. GG: OR = 0.60, 95% CI = 0.390.93,
P = 0.02). However, no significant association between this
polymorphism and TB risk was observed in other comparison
models in European group. Moreover, significant increased TB
risk was observed in dominant model (Figure 2) (AA+GA vs. GG:
OR = 0.39, 95% CI = 0.270.57, P,0.01), homozygous model
(AA vs. GG: OR = 0.31, 95% CI = 0.130.77, P = 0.01), and
heterozygous model (GA vs. GG: OR = 0.46, 95% CI = 0.32
0.68, P,0.01) in American group.
A total of 3,584 cases and 4,584 controls from 14 case-control
studies were included for data synthesis. The results showed that
there was no statistically significant association between IL-10
819C/T polymorphism and TB risk in general population (C
allele vs. T allele: OR = 0.98, 95% CI = 0.921.05, P = 0.59; CC+
TC vs. TT: OR = 1.03, 95% CI = 0.851.25, P = 0.77; CC vs.
TC+TT: OR = 0.87, 95% CI = 0.731.05, P = 0.15; CC vs. TT:
OR = 0.98, 95% CI = 0.851.12, P = 0.73; TC vs. TT: OR =
1.09, 95% CI = 0.851.41, P = 0.49) (Figure 3). In the stratified
analyses for the -819C/T polymorphism, there was a significantly
decreased risk was observed among Asians in allele model (C allele
vs. T allele: OR = 0.83, 95% CI = 0.720.96, P = 0.01),
homozygous model (CC vs. TT: OR = 0.60, 95% CI = 0.400.90,
P = 0.01), and heterozygous model (TC vs. TT: OR = 0.63, 95%
CI = 0.450.88, P = 0.006).
A total of 4,063 cases and 5,326 controls from 16 case-control
studies were included for data synthesis. In the current
metaanalysis, we did not find a significant relationship between IL-10
592A/C polymorphism and TB risk (C allele vs. A allele: OR =
0.99, 95% CI = 0.831.18, P = 0.90; CC+AC vs. AA: OR = 0.89,
95% CI = 0.741.08, P = 0.25; CC vs. AC+AA: OR = 0.92, 95%
CI = 0.781.09, P = 0.32; CC vs. AA: OR = 0.87, 95% CI = 0.68
1.11, P = 0.27; AC vs. AA: OR = 0.90, 95% CI = 0.761.07,
P = 0.24) (Figure 4). In the subgroup analysis by ethnicity, the
results indicated that there was significant association between
IL10 -592A/C polymorphism and TB risk in Asians under all gene
models (C allele vs. A allele: OR = 0.69, 95% CI = 0.570.85, P,
0.01; CC+AC vs. AA: OR = 0.65, 95% CI = 0.490.85,
P = 0.002; CC vs. AC+AA: OR = 0.62, 95% CI = 0.490.79,
P,0.01; CC vs. AA: OR = 0.49, 95% CI = 0.340.71, P,0.01;
AC vs. AA: OR = 0.70, 95% CI = 0.550.89, P,0.01), but not in
Europeans, Africans, and Americans, suggesting genetic diversity
significantly statistical evidence of publication bias under the
dominant model (-1082G/A, P = 0.992; -819T/C, P = 0.981;
592A/C, P = 0.712), which indicated low risk of publication bias in
Beggs funnel plot and Eggers test were performed to assess the
publication bias of included studies. The shapes of the funnel plots
did not reveal any evidence of obvious asymmetry under the
dominant model (-1082G/A, P = 0.953; -819T/C, P = 0.661;
592A/C, P = 0.685) (Figure. 5). Eggers test also did not show any
To date, convincing evidence indicate that the outcome of TB is
modulated by the environment as well as bacterial and host
genetic components. Many investigations have confirmed that
cytokines appear to play the critical roles in the development of
TB. Polymorphisms in several cytokine genes have been described
and demonstrated to influence gene transcription, leading to
interindividual variations in cytokine . IL-10 is a powerful T
helper 2 regulatory cytokine and plays an essential role during the
latent TB stage, where increased production of this cytokine
promotes reactivation of disease in mice  and suppression of
cell-mediated immunity against the intracellular infection .
IL10 gene is located on the long arm of chromosome 1, where
several polymorphisms have been identified within the promoter
region, such as 21082G/A, 2819T/C, and 2592A/C. Genetic
studies showed that IL-10 polymorphisms in the promoter region
were associated with TB risk, and a number of studies have been
performed to investigate that association. However, inconclusive
results were obtained. To provide further investigation into these
controversial points, a meta-analysis is needed to achieve a more
reliable and comprehensive conclusion.
Based on a meta-analysis from 18 studies that contained 4740
cases and 5919 controls, Zhang J, et al. found that -819C/T and
592A/C polymorphisms do not affect susceptibility to TB, while
the -1082G/A polymorphism was significantly associated with
decreased risk of TB only in Europeans . Our meta-analysis,
which involved 31 studies including 6559 cases and 7768 controls,
also found that the presence of the -1082G/A, -819T/C, and
592A/C genotypes was not associated with the risk of TB in the
general population. In our analysis, there was evidence of
heterogeneity between studies. It may be due to some factors,
including the ethnicity, the selection of methods, definition of
cases, and sample sizes.
As recent reports showed that genotype frequencies at IL-10
vary greatly in different populations, particularly in individuals of
different ethnicities , a subgroup analysis was conducted in our
study. Our subgroup analyses showed that the IL-10 -1082G/A
genotype significantly decreased TB risk in Europeans and
Americans, but not in Asians or Africans. The individuals who
carry variant A allele (AA+GA) had a nearly 43% and 63%
decreased risk of TB in Europeans and Americans, respectively,
suggesting a possible role of ethnic differences in genetic
backgrounds and environmental exposures. In stratified analyses
for IL-10 -819 T/C, we observed a significant association between
IL-10 -819 T/C polymorphism and TB risk in Asians under allele
model, recessive model, and homozygous model. We also observed
an association between IL-10 -592A/C polymorphism and TB risk
in Asians under all gene models. In the case of European
population, there were only 4 studies containing 284 cases and 429
controls for IL-10 -819T/C and IL-10 -592A/C polymorphisms
analysis. As for American population, there were only one study
containing 190 cases and 235 controls for IL-10 -819T/C
polymorphism analysis. Therefore, our results should be
interpreted with caution, and more case-control studies based on larger
sample size of the different ethnicity population should be carried
out in the future.
Some limitations of this meta-analysis should be considered
when explaining our results. First, given that only published
studies were included in the meta-analysis, publication bias may be
present, although our results of publication bias showed no
significance. Second, some studies were not in agreement with the
HWE, making the sample a poor representation. Third, significant
between-study heterogeneity was observed in some comparisons,
and as such, results may be distorted. Different ethnic populations
and different sources of controls may contribute to the
heterogeneity. Forth, the interaction of different susceptibility genes and
environment factors leaded to the disease, but our study could not
assess gene-gene and gene-environment interactions due to the
limited information of included studies. Last, but not the least,
meta-analysis remains a retrospective research that is subject to the
methodological deficiencies of the included studies. In view of
these limitations, further studies should focus on the associations of
gene polymorphisms and clinical or laboratory characteristic in a
large cohort of TB patients.
In conclusion, despite the several considerations mentioned
above, this meta-analysis indicated that three polymorphisms
(1082G/A, -819T/C, and -592A/C) in the IL-10 gene were not
associated with the risk of TB in general population. In the
subgroup analysis, IL-10 -1082G/A polymorphism was associated
with TB risk in Europeans and Americans, and IL-10 -819T/C
and -592A/C polymorphisms were significantly associated with
TB risk in Asians. In the future, additional large studies are
warranted to validate our findings. Future studies should include
multi-ethnic groups and use standardized unbiased genotyping
methods, and well-matched controls.
PRISMA 2009 Checklist.
Conceived and designed the experiments: BL. Performed the experiments:
BL YL. Analyzed the data: YG. Contributed reagents/materials/analysis
tools: HK. Wrote the paper: BL.
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