Cervical cancer is the second most common cancer among women worldwide.1 It is well known that the major risk factor for cervical cancer is the infection of high-risk types of human papillomavirus (HPV), but most of the infections regress without intervention, suggesting that an effective host immune response might be an important determinant of susceptibility to HPV-related cervical cancer. Cytokines, as the products of host response to inflammation, play an important role in the defense against viral infection. Interleukins are proinflammatory cytokines produced by monocytes, macrophages, and epithelial cells. The interleukin 1 (IL-1) family consists of the cytokines interleukin 1α (IL-1α), interleukin 1β (IL-1β), and a specific receptor antagonist (IL-1RN).2
Interleukin 1β is a proinflammatory cytokine mainly produced by blood monocytes and tissue macrophages and has been implicated in mediating both acute and chronic inflammation.3 Recently, a common polymorphic allele of the regulatory region of the IL-1β gene was found to be associated with increased IL-1 production.4 Individuals with high and intermediate IL-1β secretor phenotypes may be more susceptible to lower grade lesions rather than high-grade lesion or cervical carcinoma.5 Elevated IL-1β was reported to be associated with cervical dysplasia.6 These evidences suggest that IL-1β may be involved in early step of cervical carcinogenesis and that individual difference of IL-1β secretion may affect individual susceptibility to cervical cancer progression.
IL-1RN is an anti-inflammatory protein that competes with IL-1 in binding to its receptor and modulates its effects.7 The polymorphic gene that encodes IL-1RN seems to play an important role in the development of various malignancies and infectious diseases.8 The IL-1RN gene is also polymorphic due to a variable number (2–6) of tandem repeat of 86 base pair (VNTR) within its second intron.
The presence of IL-1β–511T, IL-1β–31C, and IL-1RN*2 alleles has been associated with cervical cancer risk in some reports,9–11 but not in others.12 Therefore, we did meta-analyses to find sources of variation in the reports.
MEDLINE, PubMed, EMBASE, and Wanfang were searched (last search was updated on February 10, 2014, using the search terms: “interleukin-1 receptor antagonist,” “IL1,” “polymorphism,” and “cervical cancer”). All searched studies were retrieved, and their bibliographies were checked for other relevant publications. Review articles and bibliographies of other relevant studies identified were hand-searched to find additional eligible studies. Only published studies with full text articles were included. When more than one of the same patient population was included in several publications, only the most recent or complete study was used in this meta-analysis.
The inclusion criteria were (a) evaluation of the IL-1β–511C/T, IL-1β–31T/C, and/or IL-1RN gene polymorphisms and cervical cancer risk, (b) case-control studies, and (c) sufficient published data for estimating an odds ratio (OR) with 95% confidence interval (CI).
Information was carefully extracted from all eligible publications independently by 2 of the authors according to the inclusion criteria listed previously. Disagreement was resolved by discussion between the 2 authors. If these 2 authors could not reach a consensus, another author was consulted to resolve the dispute and a final decision was made through most of the votes. The following data were collected from each study: first author’s name, publication date, ethnicity, country, total number of cases and controls, numbers of cases and controls with the IL-1β–511C/T, IL-1β–31T/C, and IL-1RN genotypes and genotype method, respectively. Different ethnicities were categorized as white and Asian. We did not define any minimum number of patients to include in our meta-analysis.
Crude ORs with 95% CIs were used to assess the strength of association between the IL-1β–511C/T, IL-1β–31T/C, and IL-1RN polymorphisms and cervical cancer risk. Pooled ORs were obtained from combination of single study homozygous model (IL-1RN: RN2/RN2 vs RN1/RN1; IL-1β–511: TT vs CC; IL-1β–31: CC vs TT), heterozygous model (IL-1RN: RN1/RN2 vs RN1/RN1; IL-1β–511: CT vs CC; IL-1β–31: CT vs TT), recessive model (IL-1RN: RN2RN2 vs RN1RN2 + RN1RN1; IL-1β–511: TT vs CT + CC; IL-1β–31: CC vs CT + TT), and dominant model (IL-1RN: RN1RN2 + RN2RN2 vs RN1RN1; IL-1β–511: TT + CT vs CC; IL-1β–31: CC + CT vs TT), respectively. Heterogeneity assumption was checked by the χ2-based Q test.13 P value greater than 0.10 for the Q test indicates a lack of heterogeneity among studies, so the pooled OR estimate of the each study was calculated by the fixed-effects model (the Mantel-Haenszel method).14 Otherwise, the random-effects model (the DerSimonian and Laird method) was used.15 An estimate of potential publication bias was carried out by the funnel plot, in which the standard error of log (OR) of each study was plotted against its log (OR). An asymmetric plot suggests a possible publication bias. Funnel plot asymmetry was assessed by the method of Egger linear regression test, a linear regression approach to measure funnel plot asymmetry on the natural logarithm scale of the OR. The significance of the intercept was determined by the t test suggested by Egger (P < 0.05 was considered representative of statistically significant publication bias).16 All the statistical tests were performed with STATA version 10.0 (Stata Corporation, College Station, TX).
One hundred eighteen studies were identified after electronic searches, and 11 articles addressed IL-1β and IL-1RN polymorphisms with cervical cancer and met the inclusion criteria9–12,17–23 (Fig. 1). Table 1 lists the studies identified and their main characteristics. For the IL-1β–511C/T polymorphism, 6 studies comprised 3 Asian and 2 white population samples. For the IL-1β–31T/C polymorphism, all subjects were Asians. For the IL-1RN polymorphism, 6 studies comprised 4 white and 2 Asian samples. All of the cases were pathologically confirmed. Controls were mainly individuals with no history of any malignancy and matched for age. Genotype distribution in the controls of each study was in agreement with Hardy-Weinberg equilibrium. Stratified analysis was only conducted for IL-1β–511C/T and IL-1RN polymorphism in Asian and white.
IL-1β–511C/T Polymorphism and Cervical Cancer Risk
Five studies compared cervical cancer cases versus controls for IL-1β–511C/T polymorphism, and forest plots of the included studies were shown in Figure 2. The overall ORs for homozygous contrast (TT vs CC: OR, 1.56; 95% CI, 1.22–1.99), heterozygous contrast (CT vs CC: OR, 1.61; 95% CI, 1.31–1.99) and dominant (TT + CT vs CC: OR, 1.60; 95% CI, 1.31–1.95) of IL-1β–511C/T polymorphism were statistically significant associated with increased risk of cervical cancer. In the subgroup analysis by ethnicity, significantly increased risks were found for whites (TT vs CC: OR, 3.08; 95% CI, 1.64–5.80; recessive: OR, 2.17; 95% CI, 1.48–3.17; and dominant: OR, 2.26; 95% CI, 1.24–4.13) and Asians (TT vs CC: OR, 1.38; 95% CI, 1.06–1.80; CT vs CC: OR, 1.62; 95% CI, 1.30–2.01; and dominant: OR, 1.54; 95% CI, 1.25–1.89).
IL-1RN Polymorphism and Cervical Cancer Risk
Meta-analysis showed that the IL-1RN polymorphism was associated with risk of cervical cancer (homozygous: OR, 2.64; 95% CI, 1.29–5.40; recessive: OR, 2.15; 95% CI, 1.06–4.38; dominant: OR, 1.60; 95% CI, 1.07–2.38). Subgroup analyses by ethnicity suggested that the IL-1RN polymorphism was associated with cervical cancer risk in whites (homozygous: OR, 3.34; 95% CI, 1.16–9.64; dominant, OR, 1.95; 95% CI, 1.19–3.02).
IL-1β–31T/C Polymorphism and Cervical Cancer Risk
No significantly elevated cervical cancer risk was found in all genetic models when all studies were pooled into the meta-analysis (CC vs TT: OR, 1.29; 95% CI, 0.98–1.69; CT vs TT: OR, 1.15; 95% CI, 0.66–1.99; recessive model: OR, 1.08; 95% CI, 0.86–1.35; and dominant model: OR, 1.96; 95% CI, 0.74–1.92).
Publication Bias and Sensitivity Analysis
Egger test was performed to access the publication bias of literatures. The results indicated no significant evidence for publication biases except for TT + CT versus CC of IL-1β–511C/T polymorphism (Table 2).
A single study involved in the meta-analysis was deleted each time to reflect the influence of the individual data set to the pooled ORs, and the corresponding pooled ORs were not materially altered (data not shown), indicating that our results were statistically robust.
Reports of IL-1β and IL-1RN polymorphisms in cervical cancer have been contradictory. The discordant results among genetic investigations of complex diseases may account for clinical heterogeneity, ethnic differences, real genetic heterogeneity, and small sample sizes.23 Meta-analysis provides a useful means of analyzing inconsistent results because it increases sample size, and thus, statistical power.24 Accordingly, the current analysis was performed to draw a more reliable conclusion compared to individual inconsistent results. Our results indicated that the association of cervical cancer with either IL-1RN polymorphism or IL-1β–511C/T polymorphism was statistically significant. However, IL-1β–31T/C polymorphism using all of the models had no associations with cervical cancer.
IL-1β is a potent activator of immune responses directed against viral and bacterial infections.25 It was recently identified to be targeted by high-risk HPV as a central hub within the network of innate immunity and down-regulated in cervical tumors.5,26 Because a gradual absence of IL-1β was also found in cervical tissue sections, inactivation of IL-1β signaling apparently inhibits its central role in the balance between inflammation and antiviral immunity against an HPV infection, thereby significantly contributing to the development of cervical cancer.27
On the basis of the previously mentioned information, we suggested that IL-1β–511C/T polymorphism could be involved in cervical cancer pathogenesis and may be a potential relevant factor for cervical cancer by affecting IL-1 production or altering levels of IL-1 gene expression.
Meanwhile, IL-1β–31T/C polymorphism could not be supposed to affect the risk of cervical cancer. However, it must be admitted that these conclusions need to be confirmed in further studies due to the limited number of participants of this meta-analysis.
IL-1RN allele 2 has been shown to be associated with increased production of IL-1RA and IL-1β and decreased production of IL-1α.10 In addition, it is reported that IL-1β overexpression correlates with mutations in the p53 gene.28 Moreover, IL-1β has been shown to reduce apoptosis by changing the ratio of BCL-2/BAX proteins.29 Therefore, higher production of IL-1β may lead to increase in p53 mutation load, and the increased level of IL-1β may play a role not only in HPV-related cervical carcinogenesis but also in HPV-nonrelated cervical carcinogenesis. Furthermore, we did find significant allele 2 of IL-1RN associations with the increased risk of overall cervical cancer among whites but not among Asians. This finding and the fact that the allele 2 is rare in Asians suggest that this genetic marker may be of less importance and effect for that ethnic group.
Some limitations of this meta-analysis should be acknowledged. First, the controls were not uniformly defined. Although most of the controls were selected mainly from healthy populations, some had benign disease. Therefore, nondifferential misclassification bias was possible because these studies may have included the control groups who have different risks of developing cervical cancer.
Second, for IL-1β–511C/T and IL-1RN polymorphisms, in the subgroup analysis, the number of each subgroup was relatively small, not having enough statistical power to explore the real association. For IL-1β–31T/C polymorphism, the number of studies involved was relatively small, so the subgroup analysis was hard to perform. Third, our results were based on unadjusted estimates, although a more precise analysis should be conducted if individual data were available, which would allow for the adjustment by other covariants including age, ethnicity, menopausal status, smoking status, drinking status, obesity, environmental factors, and lifestyle.
In summary, this meta-analysis demonstrated that the predominance of qualified studies reported a statistically significant association between IL-1β–511C/T and IL-1RN polymorphisms and cervical cancer susceptibility, and no statistically significant association between IL-1β–31T/C polymorphism and cervical cancer susceptibility. To confirm these findings, further case-control studies based on adequately sized populations, including different ethnic groups, are still needed. Moreover, further gene-gene and gene-environment interaction studies should also be considered.
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© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.