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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Keywords:© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.
Cervical cancer; Genetic susceptibility; IL-1β; IL-1RN; Polymorphism; Meta-analysis