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A R T I C L E I N F O
A B S T R A C T
Article history:
Received 7 May 2014
Received in revised form 6 August 2014
Accepted 9 September 2014
Objective: To investigate whether interleukin-10 (IL-10) polymorphisms are associated with susceptibility to pre-eclampsia.
Methods: A meta-analysis was conducted on the associations between IL-10-1082 G/A, -819 C/T and 592 C/A polymorphisms and pre-eclampsia using allele contrast, a recessive model, a dominant model
and an additive model.
Results: Thirteen groups from 11 papers involving 1534 patients with pre-eclampsia and 2271 controls
were considered in the meta-analysis. Meta-analysis of the IL-10-1082 G/A polymorphism in 3500 study
subjects revealed no association between pre-eclampsia and the IL-10-1082 G allele [odds ratio (OR) 0.890,
95% condence interval (CI) 0.7291.087; p = 0.254]. Stratication by ethnicity indicated an association
between the IL-10-1082 G allele and pre-eclampsia in the Iranian groups (OR 1.408, 95% CI 1.0971.807;
p = 0.007), but not in the European groups (OR 0.759, 95% CI 0.5061.136; p = 0.180). Meta-analysis
revealed an association between pre-eclampsia and the IL-10-819 C allele in all study subjects (OR 1.296,
95% CI 1.0121.661; p = 0.040), particularly among the Iranian groups (OR 1.390, 95% CI 1.0671.811;
p = 0.015). Meta-analysis showed no association between pre-eclampsia and the IL-10-592 C allele (OR
1.215, 95% CI 0.9671.527; p = 0.094) in any groups, except for the Iranian groups (OR 1.380, 95% CI 1.056
1.805; p = 0.018). However, the associations found in the meta-analysis became non-signicant after
exclusion of the studies in which the controls showed deviation from HardyWeinberg equilibrium.
Conclusions: This meta-analysis suggests that IL-10-1082 G/A, -819 C/T and -592 C/A polymorphisms are
unlikely to be important in susceptibility to pre-eclampsia.
2014 Elsevier Ireland Ltd. All rights reserved.
Keywords:
Pre-eclampsia
Interleukin-10
Polymorphism
Meta-analysis
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Identication of eligible studies and data extraction
Evaluations of statistical associations . . . . . . . . . . . .
Evaluation of heterogeneity and publication bias . . .
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Studies included in the meta-analysis . . . . . . . . . . . .
Meta-analysis of IL-10-1082 G/A, -819 C/T and -592
Heterogeneity, sensitivity test and publication bias .
Comment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Author queries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Condensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
* Corresponding author. Tel.: +822 920 5645; fax: +822 922 5974.
E-mail addresses: lyhcgh@korea.ac.kr, lyhcgh@naver.com (Y.H. Lee).
http://dx.doi.org/10.1016/j.ejogrb.2014.09.030
0301-2115/ 2014 Elsevier Ireland Ltd. All rights reserved.
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C/A polymorphisms and susceptibility to pre-eclampsia
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Y.H. Lee et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 182 (2014) 202207
Introduction
Pre-eclampsia is a multisystem disorder characterized by
hypertension and proteinuria after 20 weeks of gestation. It is a
leading cause of maternal and neonatal morbidity and mortality
[1]. The cause of pre-eclampsia is not fully understood; however, it
is thought to be due to suitable interactions between a susceptible
genetic background and environmental factors [2].
Interleukin-10 (IL-10) is a multifunctional cytokine with antiinammatory properties, which can downregulate antigen presentation and macrophage activation [3]. IL-10 plays an important
role in B-cell activation and auto-antibody production as a survival
and differentiation factor, and also acts as an inhibitory factor
during the production of T helper 1 cytokines [4]. IL-10 plays a key
role in balancing anti-inammatory and pro-inammatory milieu
at the fetomaternal interface. It can regulate vascular activity and
reduce inammation-mediated vascular dysfunction at the fetomaternal interface as a potent vascular cytokine [5]. IL-10 also
plays an important role in the regulation of human trophoblast
invasion [6]. Based on these known functions of IL-10, it is thought
to be involved in the pathogenesis of pre-eclampsia.
The IL-10 gene maps to 1q31-32 and exhibits polymorphisms in
its promoter region, which appear to be correlated with variations
in transcription. Three IL-10 polymorphisms have been studied in
detail: IL-10-1082 G to A (rs1800896), IL-10-819 C to T
(rs1800871) and IL-10-592 C to A (rs1800872). All three of these
polymorphisms are located at the putative regulatory regions of
the IL-10 promoter [7]. The IL-10-1082 G/A polymorphism lies
within a putative Ets transcription-factor-binding site, the IL-10819 C/T polymorphism lies within a putative positive regulatory
region, and the IL-10-592 C/A polymorphism lies within a putative
STAT-3-binding site and a negative regulatory region [8,9]. Thus,
polymorphisms at these sites may modify the transcription-factorbinding sites and affect IL-10 production. The IL-10 gene is
considered to be an attractive candidate gene for pre-eclampsia
because of its chromosomal location and functional relevance.
Several studies have examined the association between IL-10
polymorphisms and pre-eclampsia, albeit with contradictory
results, probably due to low statistical power of the individual
studies [1020]. Therefore, the authors undertook a meta-analysis
in order to overcome the limitations of interpretating individual
studies, resolve inconsistencies in reported data, and reduce the
probability of random errors that cause false-positive or falsenegative associations [2123]. Meta-analysis was used to investigate whether IL-10-1082 G/A, -819 C/T and -592 C/A polymorphisms are associated with susceptibility to pre-eclampsia.
Methods
Identication of eligible studies and data extraction
A literature search for published studies that examined the
associations between IL-10 polymorphisms and pre-eclampsia
was undertaken using MEDLINE and EMBASE; this included
articles in which IL-10 polymorphisms were analysed in patients
with pre-eclampsia. Different combinations of keywords, such as
interleukin-10, IL-10, polymorphism and pre-eclampsia, were
entered as medical subject heading components and as text words.
The references cited in the obtained papers were also examined to
identify additional studies that were not indexed by MEDLINE or
EMBASE. Genetic association studies that determined the distributions of IL-10-1082 G/A, -819 C/T and -592 C/A polymorphisms in patients with pre-eclampsia and controls were also
included. Overall, the inclusion criteria were: case-control study
design; original data; and sufcient genotype data to calculate
odds ratios (ORs). No language restrictions were applied. The
203
Y.H. Lee et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 182 (2014) 202207
204
Table 1
Characteristics of the individual studies included in the systematic review and meta-analysis.
Country
Population
Case
Control
Sowmya [10]
Sowmya [11]
Elhawary [12]
Valencia Villalvazo [13]
Vural [14]
de Lima [15]
India
India
Egypt
Mexico
Turkey
Brazil
West Asian
West Asian
Egyptian
Mexican
Turkish
Brazilian
120
88
20
411
101
92
120
100
20
613
95
101
Mirahmadian [16]
Iran
Iranian
160
100
Stonek [17]
Kamali-Sarvestani [18]
Austria
Iran
European
Iranian
107
134
107
164
Daher-1 [19]
Daher-2 [19]
Haggerty-1 [20]
Haggerty-2 [20]
Brail
Brail
USA
USA
European
Non-European
European
African American
56
94
130
21
92
97
463
199
Study
Numbers
Studied polymorphism
Findings
IL-10-819 C/T
IL-10-1082 G/A
IL-10-1082 G/A
IL-10-1082 G/A
IL-10-1082 G/A
IL-10-1082 G/A,
-819 C/T, -592 C/A
IL-10-1082 G/A,
-819 C/T, -592 C/A
IL-10-1082 G/A
IL-10-1082 G/A,
-819 C/T, -592 C/A
IL-10-1082 G/A
IL-10-1082 G/A
IL-10-1082 G/A, -819 C/T
IL-10-1082 G/A, -819 C/T
Table 2
Meta-analysis of associations between IL-10-1082 G/A polymorphisms and pre-eclampsia.
Polymorphism
Population
No. of studies
Numbers
Test of association
Test of heterogeneity
Case
Control
OR
95% CI
p-Value
Model
p-Value
I2
IL-10-1082 G/AG vs A
Overall
European
Iranian
Iranian in HWE
12
3
2
1
1375
291
282
122
2125
653
259
159
0.890
0.759
1.408
1.453
0.7291.087
0.5061.136
1.0971.807
1.0232.063
0.254
0.180
0.007
0.037
R
R
F
NA
0.801
0.041
0.805
NA
65.8
68.7
0
NA
GG vs GA + AA (recessive)
Overall
European
Iranian
Iranian in HWE
12
3
2
1
1375
291
282
122
2125
653
259
159
0.824
0.766
1.856
1.712
0.5911.149
0.5151.142
1.0653.235
0.8853.312
0.254
0.191
0.029
0.110
R
F
F
NA
0.061
0.214
0.157
NA
42.1
35.1
0
NA
GG + GA vs AA (dominant)
Overall
European
Iranian
12
3
2
1375
291
282
2125
653
259
0.924
0.699
2.371
0.7021.216
0.4271.144
0.7987.046
0.570
0.155
0.120
R
R
R
0.002
0.095
0.057
62.0
57.4
72.3
GG vs AA (additive)
Overall
European
Iranian
12
3
2
1375
291
282
2125
653
259
0.811
0.619
3.637
0.6711.125
0.2821.315
0.85215.53
0.287
0.212
0.081
R
R
R
0.001
0.095
0.065
64.8
57.4
70.7
RA, rheumatoid arthritis; R, random-effects model; F, xed-effects model; NA, not available; HWE, HardyWeinberg equilibrium.
Y.H. Lee et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 182 (2014) 202207
205
Table 3
Meta-analysis of associations between the IL-10-819 C/T and -592 C/A polymorphisms and pre-eclampsia.
Polymorphism
Population
No. of
studies
Numbers
Test of association
Test of heterogeneity
Case
Control
OR
95% CI
p-Value
Model
p-Value
I2
IL-10-819 C/T C vs T
Overall
Overall in HWE
Iranian
Iranian in HWE
6
5
2
1
529
369
291
131
1016
916
261
161
1.296
1.236
1.390
1.223
1.0121.661
0.9291.646
1.0671.811
0.8551.751
0.040
0.146
0.015
0.270
R
R
F
NA
0.046
0.044
0.302
NA
55.6
59.1
6.01
NA
CC vs CT + TT (recessive)
Overall
Overall in HWE
Iranian
Iranian in HWE
6
5
2
1
529
369
291
131
1016
916
261
161
1.572
1.442
1.745
1.373
1.0592.333
0.9330.229
1.2352.465
0.8642.162
0.025
0.100
0.002
0.180
R
R
F
NA
0.007
0.014
0.127
NA
68.4
68.1
56.9
NA
CC + CT vs TT (dominant)
Overall
Iranian
6
2
529
291
1016
261
1.071
0.984
0.7411.546
0.4792.019
0.716
0.964
F
F
0.274
0.451
21.1
0
CC vs TT (recessive)
Overall
Iranian
6
2
529
291
1016
261
1.304
1.158
0.6822.456
0.5502.441
0.412
0.699
R
F
0.074
0.594
50.2
0
IL-10-592 C/A C vs A
Overall
Iranian
Iranian in HWE
3
2
1
376
288
128
356
261
161
1.215
1.381
1.257
0.9671.527
1.0561.805
0.8751.805
0.094
0.018
0.217
F
F
NA
0.155
0.448
NA
46.4
0
NA
CC vs CA + AA (recessive)
Overall
Overall in HWE
Iranian
Iranian in HWE
3
2
2
1
376
216
288
128
356
256
261
161
1.553
1.299
1.754
1.448
1.1542.091
0.9011.871
1.2432.476
0.9082.310
0.004
0.161
0.001
0.120
F
F
F
NA
0.194
0.464
0.233
NA
38.9
0
29.8
NA
CC + CA vs AA (dominant)
Overall
Iranian
3
2
376
288
356
261
0.691
0.921
0.3851.242
0.4491.889
0.217
0.823
F
F
0.204
0.249
37.0
24.7
CC vs AA
Overall
Iranian
3
2
376
288
356
261
0.823
1.107
0.4481.514
0.5262.327
0.532
0.790
F
F
0.246
0.328
28.3
0
RA, rheumatoid arthritis; R, random-effects model; F, xed-effects model; NA, not available; HWE, HardyWeinberg equilibrium.
Fig. 1. Odds ratios and 95% condence intervals (CI) of individual studies and pooled data for the association between the G vs A allele of the IL-10-1082 G/A polymorphism
and pre-eclampsia.
206
Y.H. Lee et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 182 (2014) 202207
Fig. 2. Odds ratios and 95% condence intervals (CI) of individual studies and pooled data for the associations between the IL-10-892 C allele and pre-eclampsia (A) and the IL10-592 C allele and pre-eclampsia (B) for studies in HardyWeinberg equilibrium.
Comment
Although the multifactorial nature of pre-eclampsia is well
recognized, genetic factors are thought to be strong determinants
of this disease. IL-10 is a potent anti-inammatory cytokine that
inhibits the synthesis of pro-inammatory cytokines, and is a potent
upregulator of B-cell production and differentiation [4]. IL-10 is an
inhibitor of cytotrophoblast invasion in the uterine wall [6]. Downregulation of IL-10 expression due to hypoxia results in decreased
decidual IL-10 expression, which can affect the maternal Th2 immune
environment at the fetomaternal interface [28]. IL-10 production is
known to be decreased in placental tissue from patients with preeclampsia [29]. Reduced production of IL-10 may contribute to poor
placentation and induction of vasoactive factors [30]. IL-10 production
is determined genetically, and is controlled at the transcription level,
probably via regulatory sequences in its promoter region [31].
This meta-analysis addressed the association between IL-10
polymorphisms and susceptibility to pre-eclampsia. Data from
published studies were combined to evaluate genetic associations
between the most commonly studied polymorphisms of the IL-10
gene, namely IL-10-1082 G/A, -819 C/T and -592 C/A, polymorphisms,
and susceptibility to pre-eclampsia. This meta-analysis revealed no
association between pre-eclampsia and the IL-10-1082 G allele in all
study subjects. However, ethnicity-specic meta-analysis indicated
an association between the IL-10-1082 G allele and pre-eclampsia in
the Iranian groups. This meta-analysis also revealed an association
between pre-eclampsia and the IL-10-819 C allele among all study
subjects, as well as an association between pre-eclampsia and the
Y.H. Lee et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 182 (2014) 202207
207
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