Cervical cancer is the second most common cancer among women worldwide, 83% of these cases occurred in developing countries.1 Infection with human papillomavirus (HPV) represents the most well-established causal and risk factor for cervical cancer. Apart from HPV, the role of secondary risk factors such as smoking, oral contraceptive use, and multiparity has been discussed in the literature.2 However, in the majority of HPV-infected women, this virus is cleared by the immune system and stays only in the few individuals, with the oncogenic subtypes resulting in cervical cancer.3 This well-known information suggests that immunological, environmental, and genetic factors play an important role in the development from virus acquisition to cervical carcinoma.
Interleukin 10 (IL-10) is an immunoregulatory cytokine produced by T-helper 2 (TH2) cells, monocytes/macrophages, and regulatory T cells. It plays an important role in anti-inflammatory action by suppressing T-helper 1 (TH1) lymphocytes and stimulating B lymphocytes and TH2-lymphocytes to mediate immune responses, down-regulating the production of proinflammatory mediators such as IL-1α, IL-1β, IL-6, IL-8, IL-12, tumor necrosis factor α, interferon γ, and other proinflammatory cytokines.4 The gene encoding IL-10 is located on chromosome 1 (1q31–1q32) and is composed of 5 exons and 4 introns. Two polymorphisms in the IL-10 promoter at positions 1082 (G > A) and 592 (C > A) have effects on the expression of IL-10.5 In recent years, several studies have evaluated associations between IL-10 promoter polymorphisms and cervical cancer. The polymorphisms in IL-10 promoter influence the high-risk HPV infection clearance among immunosuppressed individuals. Interleukin 10 GCC haplotype (−1082G, −819C, −592C), whose effect has mostly been evaluated in a dominant model, is believed to encode for a higher IL-10 level. Interleukin 10 production might suppress the effects of other cytokines within the TH1-TH2 pathway and in a CD4+-dependent manner. Furthermore, beyond regulating immunity, IL-10 seems to induce the transcription of an early promoter of HPV type 16 in a significant and dose-dependent manner. However, the effects of IL-10 −1082G/A and −592C/A polymorphisms on the risks of cervical cancer are inconsistent and controversial.6,7 A single study may have been underpowered in clarifying the associations of IL-10 polymorphisms with cervical cancer susceptibility. Hence, we conducted an evidence-based quantitative meta-analysis to explore the contribution of the IL-10−1082G/A and −592C/A polymorphisms to cervical cancer susceptibility.
MATERIALS AND METHODS
PubMed, Web of Science, EMBASE, China National Knowledge Infrastructure, and Chinese Biomedical Literature database were used to search for citations published up to June 2012, with a combination of the following keywords: “cervical,” “cervix,” “cancer,” “IL-10,” “interleukin 10,” “variant,” and “polymorphism.” In addition, we checked all the references of relevant reviews and eligible articles that our search retrieved.
Inclusion and Exclusion Criteria
Studies included in our meta-analysis had to meet all of the following criteria: first, studies should concern the associations of IL-10 polymorphisms with cervical cancer risk; second, studies must offer the size of the sample, odds ratios (ORs) and their 95% confidence intervals (CIs), and the genetic distribution or the information that can help infer the results. After deliberate searching, we reviewed all articles in accordance with the criteria defined above for further analysis.
Two investigators extracted data independently and reached a consensus on all of the items. Disagreements were resolved by discussion with our research team. The studies harboring the border of the criteria were examined and determined whether they are acceptable ones on the bases of more detailed criteria that the authors implement for exceptional cases. The extracted information was entered into a database.
Meta-analysis was performed as described previously.8,9 The risk of cervical cancer associated with the −1082G/A and −592C/A polymorphism of IL-10 gene was estimated for each study by OR, together with its 95% CI. The pooled ORs were performed for the allelic, additive, dominant, and recessive models, respectively. Stratified analysis was also performed for −1082G/A and −592C/A polymorphisms. Heterogeneity assumption was made with the χ2-based Q test. If the result of the heterogeneity test was P > 0.05, ORs were pooled according to the fixed-effects model (Mantel-Haenszel). Otherwise, the random-effects model (DerSimonian and Laird) was used. Egger test and inverted funnel plots were utilized to provide a diagnosis of publication bias. All statistical tests were conducted with Stata software package (version 9.2; College Station, TX). All statistical evaluations were made assuming a 2-sided test with a significance level of 0.05, unless stated otherwise.
A total of 16 publications were identified, of which 2 irrelevant publications were discarded. Thus, 14 studies regarding IL-10 were identified. Next, 1 review and 1 study with insufficient data10,11 were excluded. Moreover, we found that 2 publications12,13 contained the same information from the same research group. Thus, 1 article with insufficient data12 was excluded. Finally, a total of 11 eligible articles6,7,13–21 were selected for this meta-analysis. Among these studies, 1 study was written in Chinese,13 and the remaining 10 were in English. A database was established according to the extracted information from each article. In Table 1, the first authors and the number of cases and controls for each study as well as other necessary information are summarized.
Of the included studies, 2 were conducted on Africans,19,21 2 on whites,17,18 2 on South Americans,15,16 and 5 were conducted on Asians. Data concerning −1082G/A polymorphism could be found in 8 included studies,6,7,13,15,16,18,19,21 and 5 studies13,14,17,18,20 provided data regarding −592C/A genetic variations. The genotype distribution in the controls of all studies was consistent with Hardy-Weinberg equilibrium (HWE) except for 2 for −1082G/A polymorphism,13,19 as shown in the Table 2.
The main results of this meta-analysis are shown in Table 3. In the overall analysis, no significant association between the IL-10 −1082G/A polymorphism and risk of cervical cancer was observed. In the subgroup analysis by ethnicity, IL-10−1082A allele was associated with decreased cervical cancer susceptibility among whites (A vs G: OR, 0.39 [95% CI, 0.32–0.47]). Studies with controls deviated from HWE showed an evident association in the dominant model (GA/AA vs GG: OR, 1.73 [95% CI, 1.04–2.89]) (Fig. 1).
With respect to −592C/A polymorphism, significantly elevated cervical cancer risk was found in the overall analysis (A vs C: OR, 1.16 [95% CI, 1.04–1.31]; AA vs CC: OR, 1.36 [95% CI, 1.00–1.84]; CA/AA vs CC: OR, 1.18 [95% CI, 1.01–1.39]; AA vs CC/CA: OR, 1.25 [95% CI, 1.01–1.55]). Stratified analysis indicated that significantly increased risks were also found among Asians in the allelic model (A vs C: OR, 1.23 [95% CI, 1.01–1.49]) (Fig. 2).
A single study involved in the meta-analysis was deleted each time to reflect the influence of individual data set to the pooled ORs, and most of the corresponding pooled ORs were not materially altered (data not shown), confirming the stability and credibility of the results.
Both Begg funnel plot and Egger test were performed to assess the publication bias of the studies. The shape of the funnel plot did not reveal any evidence of obvious asymmetry (Fig. 3). Egger test was then used to provide statistical evidence of funnel plot symmetry. The results still did not suggest any obvious evidence of publication bias for all genetic models (data not shown).
This is the first meta-analysis demonstrating a variety of associations implicating IL-10 polymorphisms and cervical cancer. Cervical cancer arises as the result of a combination of host and environmental factors.15 Previously, genetic factors are considered as important factors in the development of cervical cancer.22 Polymorphism in cytokine genes can influence immune response to HPV infection, possibly modifying the risk of cervical cancer.21,23
Interleukin 10 is a potent pleiotropic cytokine that plays an important role in immunological and inflammatory responses, as it regulates B-cell proliferation and differentiation, and exhibits immunoregulatory activities and anti-inflammatory properties.24 In recent years, a number of case-control studies were performed to assess the effects of IL-10 gene polymorphisms on disease risk. Nevertheless, to date, because of small sample sizes, unified ethnicity, and low statistical power of individual studies, there are some controversial results of associations between IL-10 polymorphisms and cervical cancer. It has been shown that IL-10 −1082G/A polymorphisms are not associated with an increased risk of cervical cancer,6 whereas a previous study indicated that the polymorphism may serve as a marker of genetic susceptibility to cervical cancer among Japanese women.7
In this study, we performed the first meta-analysis upon the 2 most focused polymorphisms of IL-10 gene (−1082G/A and −592C/A) to clarify the effect of IL-10 polymorphisms on the risk of cervical cancer. Information regarding −1082G/A polymorphism could be available from 8 studies. The pooled data failed to suggest the association of −1082G/A polymorphism with cervical carcinoma. In subgroup analysis according to HWE, a significant difference was observed between the “HWE Yes” and “HWE No” subgroup, indicating that selection of the HWE might have an evident influence. Thus, the IL-10−1082A allele might have some influence on cervical tumorigenesis. At the same time, we suggested the association of −592C/A polymorphism with cervical cancer. Moreover, stratified analysis indicated that significantly increased risks were also found among Asians but not among whites in the allelic model. It is well known that the distribution of malignant HPV subtypes is different between whites and Asians. The different HPV subtypes may account for the different cervical cancer risks in subgroup analyses. A variety of human neoplasia is characterized by secretion of high levels of IL-10, which suggests a poor host immune response to the tumor and the suppression of tumor-infiltrating lymphocyte effector function.11 Thus, the underlying mechanism of IL-10 in the pathogenesis of cervical cancer may be related to IL-10 inhibition of T-cell activation, inducing preferential priming of type 2 cytokine-secreting lymphocytes, suppressing the expression of major histocompatibility complex classes I and II antigens.25
However, several limitations might be included in this study. First, the number of cases and controls in the included studies was limited. Second, subgroup analyses concerning other risk factors such as smoking status and HPV infection have not been included in the present study because of insufficient data from the primary literature. Third, further studies estimating the effect of gene-environment interactions may eventually provide a better, comprehensive understanding of the association between the IL-10 polymorphisms and cervical cancer risk.
In conclusion, the overall data of the present meta-analysis showed no effect of the IL-10 −1082G/A polymorphism and the clear association of the IL-10 −592C/A polymorphism with cervical cancer risk. However, the IL-10 −592 A allele might increase cervical carcinoma susceptibility among Asians but not among whites. Further well-designed studies with large sample sizes are warranted to confirm our findings.
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Keywords:Copyright © 2013 by IGCS and ESGO
IL-10; Cervical cancer; Polymorphism; Meta-analysis