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European Journal of Obstetrics & Gynecology and Reproductive Biology 182 (2014) 202207

Contents lists available at ScienceDirect

European Journal of Obstetrics & Gynecology and


Reproductive Biology
journal homepage: www.elsevier.com/locate/ejogrb

Review

Meta-analysis of associations between interleukin-10 polymorphisms


and susceptibility to pre-eclampsia
Y.H. Lee *, J.-H. Kim, G.G. Song
Division of Rheumatology, Department of Internal Medicine, Korea University College of Medicine, Anam-Dong, Seoul, Republic of Korea

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

exclusion criteria were: overlapping data; inability to ascertain the


number of null and wild genotypes; and studies of family
members, because the analysis was based on linkage considerations. Two independent reviewers extracted the data on the
methods and results from the original studies for meta-analysis.
Any discrepancies were resolved by consensus between the two
reviewers or by intervention of a third reviewer. The following
information was extracted from each study: author name; year of
publication; ethnicity of the study population; demographics;
number of cases and controls; and genotype and allele frequencies
of IL-10-1082 G/A, -819 C/T and -592 C/A polymorphisms.
Evaluations of statistical associations
Allele frequencies of IL-10 polymorphisms were determined
using the allele counting method. Chi-squared test was used to
ascertain whether the observed frequencies of genotypes in the
controls conformed to HardyWeinberg equilibrium (HWE). Metaanalyses were performed using allelic contrast, and recessive,
dominant and additive models. Point estimates of risks, ORs and
95% condence intervals (CI) were estimated for each study.
Cochrans Q-statistic was used to assess within- and betweenstudy variations and heterogeneities. This heterogeneity test
assesses the null hypothesis that all studies evaluated the same
effect. The effect of heterogeneity was quantied using I2, which
ranges from 0 to 100% and represents the proportion of betweenstudy variability attributable to heterogeneity rather than to
chance [24]. I2 values of 25%, 50% and 75% were nominally
considered as low, moderate and high estimates, respectively. The
xed-effects model assumes that a genetic factor has a similar
effect on susceptibility to pre-eclampsia across all investigated
studies, and that the observed variations between the studies are
caused by chance alone [25]. However, the random-effects model
assumes that different studies show substantial diversity, and
assesses both within-study sampling errors and between-study
variances [26]. When the study groups are homogeneous, the two
models are similar. In contrast, when the groups are not
homogeneous, the random-effects model usually provides wider
CIs than the xed-effects model. The random-effects model is best
used in the presence of signicant between-study heterogeneity
[26]. Statistical manipulations were performed using the Comprehensive Meta-Analysis program (Biostat, Englewood, NJ, USA).
Evaluation of heterogeneity and publication bias
Sensitivity analysis was performed to assess the inuence of
each individual study on the pooled OR by omitting each individual
study, and to investigate statistically robust results from this metaanalysis. To examine the potential source of heterogeneity
observed in this meta-analysis, meta-regression was performed
using HWE, ethnicity, publication year and sample size. While
funnel plots are often used to detect publication bias, funnel
plotting requires diverse study types of varying sample sizes and
involves subjective judgements. Accordingly, this study evaluated
any publication bias using Eggers linear regression test [27], which
measures funnel plot asymmetry using a natural logarithm scale of
ORs.
Results
Studies included in the meta-analysis
Fifty-ve studies were identied by electronic and manual
searches, and 15 studies were selected for full-text review based on
the title and abstract details. Four studies were excluded because
they discussed IL-10 polymorphisms other than those considered

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

IL-10-819 C allele (p = 0.0003)


NS
IL-10-1082 G allele (p = 0.003)
NS
IL-10-1082 G allele (p = 0.04)
NS
IL-10-1082 G/A (NS), -819 C/T (p = 0.001),
-592 C/A (p = 0.001)
NS
IL-10-1082 G/A (p = 0.045), -819 C/T (NS),
-592 C/A (NS)
IL-10-1082 G/A (p = 0.02)
NS
NS
NS

NS, not signicant.

in this study, showed data duplication, or had insufcient data.


Thus, only 11 studies met the inclusion criteria [1020], two of
which contained data on two different groups [19,20] which were
analysed separately. Finally, 13 separate comparisons were
considered in this meta-analysis, which involved 1534 patients
with pre-eclampsia and 2271 controls from three European
populations, two Iranian populations, two West Asian populations,
one Egyptian population, one Mexican population, one Brazilian
population, one African American population and one nonEuropean population (Table 1). However, because the populations
from each ethnic group were inadequate, ethnicity-specic metaanalysis was only conducted on the European and Iranian
populations. Details of the IL-10 polymorphisms studied are
summarized in Table 1.
Meta-analysis of IL-10-1082 G/A, -819 C/T and -592 C/A
polymorphisms and susceptibility to pre-eclampsia
A summary of the meta-analysis ndings concerning associations between IL-10 polymorphisms and pre-eclampsia is provided
in Tables 2 and 3. Meta-analysis of the IL-10-1082 G/A polymorphism in the 3500 study subjects revealed no association between
pre-eclampsia and the IL-10-1082 G allele (OR 0.890, 95% CI 0.729
1.087; p = 0.254) (Table 2, Fig. 1). 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 0.506
1.136; p = 0.180) (Table 2). A similar pattern was noted for the IL10-1082 G allele using the recessive model (Table 2). No
association was recorded between pre-eclampsia and the IL-101082 G/A polymorphism using the dominant model or contrast of
homozygotes (Table 2). However, meta-analysis after the exclusion of two studies that showed deviation from HWE showed no
relationship between the IL-10-1082 G/A polymorphism and preeclampsia in the Iranian groups (OR 1.712, 95% CI 0.8853.312;
p = 0.110) (Table 2). Although a single Iranian study in HWE
revealed an association between the IL-10-1082 G allele and preeclampsia (OR 1.453, 95% CI 1.0232.063; p = 0.037), this was the
nding of a single study, rather than a meta-analysis (Table 2).
Meta-analysis of the IL-10-819 C/T polymorphism in all study
subjects revealed an association between pre-eclampsia and the
IL-10-819 C allele (OR 1.296, 95% CI 1.0121.661; p = 0.040)
(Table 3). Stratication by ethnicity indicated an association
between the IL-10-819 C allele and pre-eclampsia in the Iranian
groups (OR 1.390, 95% CI 1.0671.811; p = 0.015) (Table 3).
However, the results of meta-analysis, after exclusion of the
studies that had controls which deviated from HWE, revealed no
association between the IL-10-819 C allele and pre-eclampsia for
cumulative studies (OR 1.236, 95% CI 0.9291.646; p = 0.146),
particularly for the Iranian groups (OR 1.223, 95% CI 0.8551.751;

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.

p = 0.270) (Table 3, Fig. 2). Analysis using the recessive model


showed the same pattern for the IL-10-819 C allele (Table 3). No
association was found between pre-eclampsia and the IL-10-819
C/T polymorphism using the dominant model or contrast of
homozygotes (Table 3). Meta-analysis of the IL-10-592 C/A
polymorphism for all study subjects revealed no association
between pre-eclampsia and the IL-10-592 C allele (OR 1.215, 95%
CI 0.9671.527; p = 0.094) (Table 3, Fig. 2). However, stratication

by ethnicity indicated an association between the IL-10-592 C


allele and pre-eclampsia in the Iranian groups (OR 1.380, 95% CI
1.0561.805; p = 0.018) (Table 3). Analysis after excluding the
Iranian study showed deviation from HWE and no association
between the IL-10-592 C/T polymorphism and pre-eclampsia (OR
1.257, 95% CI 0.8751.805; p = 0.217) (Table 3). A similar pattern
was obtained for the IL-10-592 C allele using the recessive model
(Table 3). No association was found between pre-eclampsia and

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.

the IL-10-592 C/A polymorphism using the dominant model or


contrast of homozygotes (Table 3).
Heterogeneity, sensitivity test and publication bias
Some heterogeneity was noted in the meta-analysis of the IL10-1082 G/A and -819 C/T polymorphisms (Tables 2 and 3). Metaregression was performed to examine the potential sources of
heterogeneity in the meta-analysis. The results showed that,
among all studied factors, the publication year (p = 0.022) had a
signicant impact on heterogeneity for the IL-10-819 C/T
polymorphism. Recent studies have strengthened the pooled OR
for the IL-10-819 C/T polymorphism in pre-eclampsia. Sensitivity
analysis revealed that some individual studies had a signicant
effect on the pooled or, resulting in meta-analysis results that were
not statistically robust. The distributions of genotypes in the
normal control groups were not consistent with HWE in two
studies of the IL-10-1082 G/A polymorphism [10,16], one study of
the IL-10-819 C/T polymorphism [16] and one study of the IL-10592 C/A polymorphism [16]. Deviation from HWE among controls
implies a potential bias during control selection or genotyping
errors; exclusion of these studies did affect the result regarding
associations between IL-10-1082 G/A, -819 C/T and -592 C/A
polymorphisms and pre-eclampsia (Tables 2 and 3). It was difcult
to correlate the funnel plot, which is usually used to detect
publication bias, because of the small number of studies included
in this analysis. However, Eggers regression test showed no
evidence of publication bias (Eggers regression test, p > 0.1).

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

IL-10-592 C allele in the Iranian groups. As deviation from HWE


among the controls implied potential bias during control selection or
genotyping errors, subgroup analysis was reperformed for studies in
HWE. The associations found in the meta-analysis were not signicant
after exclusion of the studies that had controls which deviated from
HWE. Therefore, this meta-analysis suggests that IL-10-1082 G/A, 819 C/T and -592 C/A polymorphisms are unlikely to be major genetic
factors in susceptibility to pre-eclampsia.
This meta-analysis counters the belief that IL-10 polymorphisms play an important role in susceptibility to pre-eclampsia.
However, these results should be interpreted with caution because
of the limited number of studies included and the heterogeneity
therein. The meta-analysis results of IL-10 polymorphisms are not
consistent with the results of functional studies of IL-10
polymorphisms. It is not uncommon for epidemiological results
to contrast with the results of functional studies, because preeclampsia is a complex disease and its development is inuenced
by multiple genes, different genetic backgrounds and environmental factors. The results of this meta-analysis for IL-10
polymorphisms may be due to type II error (false-negative).
The present study has some limitations that require consideration.
First, heterogeneity and confounding factors may have distorted the
meta-analysis. Furthermore, publication bias may also have affected
the analysis, because studies that produced negative results may not
have been published or may have been missed during the data search.
However, if studies with negative results were included, the lack of
association between pre-eclampsia and IL-10 would not turn into a
positive association. Second, this ethnicity-specic meta-analysis
included data from European and Iranian patients; thus, the results
are only applicable to these ethnic groups. Further studies are needed
in various ethnic groups. Third, haplotype analysis may have provided
more information and would have been more powerful than single
polymorphism analysis. Linkage disequilibrium was found for IL-101082 G/A, -819 C/T and -592 C/A polymorphisms. Meta-analysis of
haplotypes was not possible due to the inadequacy of haplotype data.
Finally, inadequate data hindered examination of an association
between IL-10 polymorphisms and the activity or clinical features of
pre-eclampsia.
In conclusion, this meta-analysis suggests that IL-10-1082 G/A, 819 C/T and -592 C/A polymorphisms may be not associated with
susceptibility to pre-eclampsia. These data do not support the
assumption that IL-10-1082 G/A, -819 C/T and -592 C/A polymorphisms play an important role in susceptibility to pre-eclampsia.
Large-scale studies of homogenous population groups belonging to
different ethnicities are necessary to investigate the roles of these IL10 polymorphisms in susceptibility to pre-eclampsia.
Conict of interest
None declared.
Funding
None declared.
Author queries
This article has been edited extensivelyplease check the
proofs carefully to ensure that your meaning has not been altered.
Condensation
IL-10-1082 G/A, -819 C/T and -592 C/A polymorphisms are
unlikely to be important in susceptibility to pre-eclampsia.

207

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