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Open Access

Peer-reviewed

Research Article

Tumor Necrosis Factor Alpha rs1800629 Polymorphism and Risk of Cervical Lesions: A Meta-Analysis

  • Min Li,

    Affiliations Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, Department of Obstetrics and Gynecology, South Branch of the Six People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China

    ⨯
  • Ying Han,

    Affiliation Department of Obstetrics and Gynecology, South Branch of the Six People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China

    ⨯
  • Ting-Ting Wu,

    Affiliation Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    ⨯
  • Yichen Feng,

    Affiliation Department of Obstetrics and Gynecology, South Branch of the Six People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China

    ⨯
  • Hong-Bo Wang

    shanghsunn@126.com

    Affiliation Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    ⨯

Abstract

Background

Tumor necrosis factor- alpha (TNF-α) is an inflammatory cytokine which may play important role on the immune response may control the progression of cervical lesions. There is a possible association between TNF-α rs1800629 G/A polymorphism and cervical lesions, but previous studies report conflicting results. We performed a meta-analysis to comprehensively assess the association between TNF-α rs1800629 polymorphism and cervical lesions risk.

Methods

Literature searches of Pubmed, Embase, Web of Science, and Wanfang databases were performed for all publications on the association between TNF-α rs1800629 polymorphism and cervical lesions through December 15, 2012. The pooled odds ratios (ORs) with their 95% confidence interval (95%CIs) were calculated to assess the strength of the association.

Results

Twenty individual case-control studies from 19 publications with a total of 4,146 cases and 4,731 controls were finally included into the meta-analysis. Overall, TNF-α rs1800629 polymorphism was significantly associated with increased risk of cervical lesions under two main genetic comparison models (For A versus G: OR 1.22, 95%CI 1.04–1.44, P = 0.017; for AA versus GG: OR 1.32, 95%CI 1.02–1.71, P = 0.034). Subgroup analysis by ethnicity further showed that there was a significant association between TNF-α rs1800629 polymorphism and increased risk of cervical lesions in Caucasians but not in Asians. Subgroup analysis by the types of cervical lesions showed that there was a significant association between TNF-α rs1800629 polymorphism and increased risk of cervical cancer (For A versus G: OR 1.24, 95%CI 1.05–1.47, P = 0.011; for AA versus GG: OR 1.31, 95%CI 1.01–1.70, P = 0.043; for AA/GA versus GG: OR 1.25, 95%CI 1.01–1.54, P = 0.039).

Conclusion

The meta-analysis suggests that TNF-α rs1800629 polymorphism is associated with increased risk of cervical lesions, especially in Caucasians.

Citation: Li M, Han Y, Wu T-T, Feng Y, Wang H-B (2013) Tumor Necrosis Factor Alpha rs1800629 Polymorphism and Risk of Cervical Lesions: A Meta-Analysis. PLoS ONE 8(8): e69201. https://doi.org/10.1371/journal.pone.0069201

Editor: Rui Medeiros, IPO, Inst Port Oncology, Portugal

Received: January 29, 2013; Accepted: June 6, 2013; Published: August 27, 2013

Copyright: © 2013 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The authors have no support or funding to report.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Cervical cancer is the third most common cancer and the fourth leading cause of cancer death among females, accounting for nearly 10% of the total newly-diagnosed cancer cases and 8% of the total cancer deaths [1]. Global incidence of cervical cancer has increased from about 378,000 cases per year in 1980 to about 454,000 cases per year in 2010 [2]. Risk factors of cervical cancer include human papillomavirus (HPV) and smoking, and infection of carcinogenic HPV is a main cause of almost all cases with cervical lesions [3]. Preinvasive lesions of cervical cancer have also been classified in terms of squamous intraepithelial lesions (SILs). Cervical cancer is considered to be a preventable disease because of its relatively long period of precancerous lesions, such as cervical intraepithelial neoplasia (CIN) [4]. Several cytokines that modulate the immunologic response have been implicated in the development of cervical cancer [5]–[7]. It has been well accepted that cervical cancer is mainly initiated by HPV infection, and tumor necrosis factor-alpha (TNF-α) is an inflammatory cytokine which may play important roles in the immune response of cervical lesions [5], [7]. TNF-α is located on chromosome 6 (region p21.3), and it is a potent proinflammatory cytokine playing an important role in the development of the immune response [5], [6]. Currently, there are several common single nucleotide polymorphisms (SNP) in the TNF-α gene which can regulate the transcription and production of TNF-α, such as TNF-α rs1800629 and TNF-α rs361525 [8], [9]. TNF-α rs1800629 is the most studied polymorphism, which is a G to A transition in the promoter at position −308 and is associated with the level of TNF-α expression [10], [11]. Therefore, TNF-α rs1800629 polymorphism may be related with risk of cervical lesions [10], [11]. However, results from previous studies examining the association between TNF-α rs1800629 polymorphism and risk of cervical lesions were contradictory [12]–[25]. These inconclusive results may due to the limited sample size of single study or the different characteristics among studies, such as ethnicity, pathological types, and sources of controls. Therefore, we performed a meta-analysis to comprehensively assess the association between TNF-α rs1800629 polymorphism and cervical lesions risk.

Methods

Search strategy

An electronic search of the Pubmed, Embase, Web of Science, and Wanfang databases was performed to identify the eligible studies assessing the association between TNF-α rs1800629 polymorphism and risk of cervical lesions. There were no language restrictions and the last search time was the November 16, 2012. We used the keywords and subject terms: (“cervical carcinoma”, “cervical cancer”, “cervix carcinoma” or “cervix cancer” or cervical neoplasm, cervical lesions, cervical lesion, cervical intraepithelial lesion, cervical intraepithelial lesions, cervical dysplasia, cervical intraepithelial neoplasia) and (“polymorphism” or “variant” or “genotype” or “mutation” or) and (“tumor necrosis factor” or “TNF” or “308 G/A” or “TNF-α” or “rs1800629”). All eligible studies were retrieved, and their bibliographies were checked for other relevant publications.

Inclusion criteria and exclusion criteria

To be eligible for the inclusion criteria in the meta-analysis, the following criteria were used: 1) case-control studies comparing cervical lesions cases with healthy or non-cancer controls; 2) studies evaluating the association between TNF-α rs1800629 polymorphism and risk of cervical lesions; 3) Sufficient genotype data of TNF-α rs1800629 polymorphism were reported. 4) Studies was excluded if they were the following: 1) Case-only studies; 2) Case reports, letters, or reviews; 3) Incomplete data or no usable data were reported; 4) Studies containing overlapping data; 5) Family-based design or related cases and controls were contained.

Data extraction and quality assessment

The data extraction was performed independently by two reviewers, and the conflicting data extracted were settled by discussion. A standardized form was used in the data extraction from the published studies, and the following data were extracted: first author, year of publication, country, ethnicity, study design, diagnostic criteria, source of cases and controls, number of cases and controls, types of cervical lesions, genotyping methods, frequencies of TNF-α rs1800629 genotypes, and the confirmation of Hardy-Weinberg equilibrium (HWE) in controls. The quality of included studies was assessed by the confirmation of HWE in controls, and studies without the confirmation of HWE in controls were defined as low-quality studies, while studies with the confirmation of HWE in controls were defined as high-quality studies.

Statistical analysis

Before the effect estimation of associations between the TNF-α rs1800629 polymorphism and risk of cervical lesions, we firstly tested whether the genotype frequencies of TNF-α rs1800629 genotypes in the controls were confirmed with HWE using the χ2 test. The strength of the associations between the TNF-α rs1800629 polymorphism and risk of cervical lesions was estimated using odds ratios (ORs) and their 95% confidence interval (95%CIs). The following contrasts for the associations between the TNF-α rs1800629 polymorphism and risk of cervical lesions were evaluated: comparison of the variant allele with ancestral allele (A vs. G); comparison of the variant homozygote with the ancestral homozygote (AA vs. GG); comparison of the variant homozygote combined with the heterozygote vs. ancestral homozygote (AA/GA vs. GG); comparison of the variant homozygote vs. ancestral homozygote combined with the heterozygote (AA vs. GA/GG). The I2 statistic to quantify the proportion of the total variation due to heterogeneity were calculated, and a I2 value of more than 50% was interpreted as significant heterogeneity among studies [26]. When the effects were assumed to be homogenous, the fixed-effects model was used (Mantel-Haenszel method) [27]. If obvious heterogeneity was present, the random-effects model was used (DerSimonian-Laird method) [28]. Subgroup analysis based on ethnicity was used to explore the possible race-specific effect in the association. Subgroup analyses based on the types of cervical lesions and the quality of included studies were also performed. Potential publication bias was assessed by visual inspection of the funnel plots, in which the standard error of logOR of each study was plotted against its logOR, and an asymmetric plot suggested possible publication bias. In addition, We also performed Egger linear regression test at the P<0.05 level of significance to assess the funnel-plot's asymmetry [29]. All analyses were conducted using STATA (Version 11, StataCorp, College Station, TX). All P-values in the meta-analysis were two-sided, and statistical significance was considered when the P-value was less than 0.05.

Results

Study selection and description of included studies

A total of 117 potentially individual abstracts were found from the the Pubmed, Embase, Web of Science, and Wanfang databases, but only 24 studies were preliminarily identified and were further assessed for inclusion [13]–[25], [30]–[39] (Figure 1). After reviewing the full-texts of those 25 studies, three studies were excluded for irrelevant studies [36], [37], [39] and two were excluded for studies assessing the other TNF gene polymorphisms [35], [38]. Since the research by Kohaar et al. assessed the associations of TNF-α rs1800629 polymorphism with risks of both cervical cancer and squamous intraepithelial lesions, the data were extracted as two individual studies [21]. Therefore, twenty individual case-control studies from 19 publications with a total of 4,146 cases and 4,731 controls were finally included into the meta-analysis [13]–[25], [30]–[34]. The main characteristics of those twenty studies on the association between TNF-α rs1800629 polymorphism and cervical lesions risk were listed in the Table 1. There were 11 studies from Caucasians, 5 studies from Asians, and 4 ones form mixed populations. Among those 20 studies, most studies 17 studies (85.0%) were about the association between TNF-α rs1800629 polymorphism and invasive cervical cancer, while the left 3 ones were about the association between TNF-α rs1800629 polymorphism and squamous intraepithelial lesions. In addition, 15 from those 20 studies had the confirmation of HWE in controls and were defined as high-quality studies.

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Figure 1. Flow chart of study selection in the meta-analysis of the association between TNF-α rs1800629 polymorphism and cervical lesions risk.

https://doi.org/10.1371/journal.pone.0069201.g001

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Table 1. Characteristics of twenty studies on the association between TNF-α rs1800629 polymorphism and cervical lesions risk.

https://doi.org/10.1371/journal.pone.0069201.t001

Meta-analysis

Meta-analysis of all 20 studies showed that there was a significant association between TNF-α rs1800629 polymorphism and cervical lesions risk under two main genetic comparison models (For A versus G: OR 1.22, 95%CI 1.04–1.44, P = 0.017; for AA versus GG: OR 1.32, 95%CI 1.02–1.71, P = 0.034) (Table 2, Figure 2).

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Figure 2. Forest plot describing the association between TNF-α rs1800629 polymorphism and cervical lesions risk.

(Each study is shown by the point estimate of the OR and 95% CI, and (the size of the square is proportional to the weight of each study.) Figure 2-(A) A vs. G. Figure 2- (B) AA vs. GG. Figure 2- (C) AA/GA vs. GG.

https://doi.org/10.1371/journal.pone.0069201.g002

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Table 2. Meta-analysis of the association between TNF-α rs1800629 polymorphism and cervical lesions risk.

https://doi.org/10.1371/journal.pone.0069201.t002

Subgroup analysis of studies with high quality showed that there was still a significant association between TNF-α rs1800629 polymorphism and increased risk of cervical lesions under two main genetic comparison models (for AA versus GG: OR 1.81, 95%CI 1.26–2.61, P = 0.001; for AA versus GA/GG: OR 1.86, 95%CI 1.29–2.68, P = 0.001) (Table 2). However, in the subgroup analysis of studies with low quality, there was no association between TNF-α rs1800629 polymorphism and increased risk of cervical lesions (Table 2).

Subgroup analysis of Caucasians showed that there was a significant association between TNF-α rs1800629 polymorphism and increased risk of cervical lesions under all four genetic models (For A versus G: OR 1.33, 95%CI 1.07–1.65, P = 0.009; for AA versus GG: OR 1.47, 95%CI 1.08–2.00, P = 0.015; for GA/AA versus GG: OR 1.26, 95%CI 1.01–1.58, P = 0.045; for AA versus GA/GG: OR 1.45, 95%CI 1.06–1.97, P = 0.018). However, subgroup analysis of Asians showed that there was no association between TNF-α rs1800629 polymorphism and increased risk of cervical lesions in Asians (Table 2).

Subgroup analysis by the types of cervical lesions showed that there was a significant association between TNF-α rs1800629 polymorphism and increased risk of cervical cancer (For A versus G: OR 1.24, 95%CI 1.05–1.47, P = 0.011; for AA versus GG: OR 1.31, 95%CI 1.01–1.70, P = 0.043; for AA/GA versus GG: OR 1.25, 95%CI 1.01–1.54, P = 0.039). But there was no association between TNF-α rs1800629 polymorphism and risk of squamous intraepithelial lesions (Table 2).

Publication bias

Publication bias was investigated by Begg's funnel plot, and funnel plot asymetry was further assessed by Egger's linear regeression test. As shown in the Figure 3, there was low possibility of asymmetry in the allele comparison model (A versus G) of this meta-analysis (Figure 3). Besides, the Egger linear regression test also suggested there was no significant risk of publication bias (P = 0.532). Therefore, there was no risk of publication bias in the meta-analysis.

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Figure 3. Funnel plot for the detection of the publication bias in this meta-analysis.

https://doi.org/10.1371/journal.pone.0069201.g003

Discussion

Cervical cancer is mainly initiated by HPV infection, and TNF-α is an inflammatory cytokine which may play important roles in the progression of cervical lesions [3], [5]. There is a possible association between TNF-α rs1800629 G/A polymorphism and risk of cervical lesions, but previous studies report conflicting results [12]–[25]. We performed a meta-analysis to comprehensively assess the association between TNF-α rs1800629 polymorphism and cervical lesions risk. Twenty case-control studies with a total of 4,146 cases and 4,731 controls were finally included into the meta-analysis [13]–[25], [30]–[34]. Overall, TNF-α rs1800629 polymorphism was significantly associated with increased risk of cervical lesions under two main genetic comparison models (Table 2). Subgroup analysis by ethnicity further showed that there was a significant association between TNF-α rs1800629 polymorphism and increased risk of cervical lesions in Caucasians but not in Asians (Table 2). Subgroup analysis by the types of cervical lesions showed that there was a significant association between TNF-α rs1800629 polymorphism and increased risk of cervical cancer (Table 2). Therefore, the meta-analysis suggests that TNF-α rs1800629 polymorphism is associated with increased risk of cervical lesions, especially in Caucasians.

Cervical cancer is the third most common cancer and the fourth leading cause of cancer death among female in the world. In recent years, the incidence of cervical cancer has increased gradually [2]. Since cervical cancer is considered to be a preventable disease because of its relatively long period of precancerous lesions, identifications of risk factors of cervical lesions can help us find some effective and preventive interventions. It has been well accepted that HPV and smoking are main causes of almost all cases with cervical lesions, and the genetic factors also play important roles in the development of cervical lesions [3]. Currently, several genetic polymorphisms have been suggested to be associated with risk of cervical cancer, such as p53 Arg72Pro mutation and MTHFR gene polymorphisms [40]–[42].

TNF-α is secreted mainly by activated macrophages, which is an extraordinarily pleiotropic cytokine with a central role in immune homeostasis, inflammation, and host defense [5]. The development of cervical cancer is induced by persistent HPV infection, and TNF-α may be involved in the susceptibility to HPV infection and development of cervical cancer by modulating viral replication [5]. TNF-α rs1800629 is the most studied polymorphism, which is a G to A transition in the promoter at position −308 and is associated with the level of TNF-α expression [10], [11]. Although a possible association of the TNF-α rs1800629 polymorphism with risk of cervical lesions was reported, and many case-control studies were further performed to identify the association, it was still unknown whether there was a significant association between TNF-α rs1800629 polymorphism and risk of cervical lesions [13]–[25], [30]–[34]. In current meta-analysis, we conducted a systematic review and meta-analysis of previous published case-control studies to comprehensively evaluate the association between TNF-α rs1800629 polymorphism and cervical lesions risk. The findings from the meta-analysis suggest that TNF-α rs1800629 polymorphism is associated with increased risk of cervical lesions and TNF-α plays an important role in the development of cervical cancer.

There were some limitations in our meta-analysis. Firstly, there was limited number of eligible studies in the meta-analysis of the association between TNF-α rs1800629 polymorphism and risk of squamous intraepithelial lesions. The limited sample size in the meta-analysis may fail to provide enough statistical power to detect a possible or weak effect of TNF-α rs1800629 polymorphism on squamous intraepithelial lesions. Therefore, more studies with large sample are needed to give a more precise estimation of the association between TNF-α rs1800629 polymorphism and risk of squamous intraepithelial lesions. Secondly, the meta-analysis was based on unadjusted data, as the ORs adjusted for the main confounding variables were not available from those studies. To provide a more reliable estimation of the association, more studies with well-design and large sample size are needed to further identify the association. Finally, gene-gene interactions were not fully addressed in the meta-analysis for the lack of relevant data. There are several polymorphisms associated with risk of cervical cancer, such as p53 Arg72Pro mutation and MTHFR gene polymorphisms [40]–[42]. But no studies investigated the gene-gene interactions in the association between TNF-α rs1800629 polymorphism and risk of cervical lesions. Future studies may further assess the possible gene-gene interactions in the association between TNF-α rs1800629 polymorphism and risk of cervical lesions.

In summary, our meta-analysis suggests that TNF-α rs1800629 polymorphism is associated with increased risk of cervical lesions, especially in Caucasians. However, more studies with large sample and well-design are needed to give a more reliable estimation of the association between TNF-α rs1800629 polymorphism is associated and risk of cervical lesions.

Supporting Information

Checklist S1.

PRISMA 2009 checklist.

https://doi.org/10.1371/journal.pone.0069201.s001

(DOC)

Author Contributions

Conceived and designed the experiments: ML HBW. Performed the experiments: ML YH YF HBW. Analyzed the data: ML TTW HBW. Contributed reagents/materials/analysis tools: ML YH TTW YF HBW. Wrote the paper: ML HBW.

References

  1. 1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, et al. (2011) Global cancer statistics. CA Cancer J Clin 61(2): 69–90.
  2. 2. Forouzanfar MH, Foreman KJ, Delossantos AM, Lozano R, Lopez AD, et al. (2011) Breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis. Lancet 378(9801): 1461–84.
  3. 3. Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S (2007) Human papillomavirus and cervical cancer. Lancet 370(9590): 890–907.
  4. 4. Kahn JA (2009) HPV vaccination for the prevention of cervical intraepithelial neoplasia. N Engl J Med 361(3): 271–8.
  5. 5. Balkwill F (2009) Tumour necrosis factor and cancer. Nat Rev Cancer 9(5): 361–71.
  6. 6. Lobito AA, Gabriel TL, Medema JP, Kimberley FC (2011) Disease causing mutations in the TNF and TNFR superfamilies: Focus on molecular mechanisms driving disease. Trends Mol Med 17(9): 494–505.
  7. 7. Walczak H (2011) TNF and ubiquitin at the crossroads of gene activation, cell death, inflammation, and cancer. Immunol Rev 244(1): 9–28.
  8. 8. Fargion S, Valenti L, Dongiovanni P, Scaccabarozzi A, Fracanzani AL, et al. (2001) Tumor necrosis factor alpha promoter polymorphisms influence the phenotypic expression of hereditary hemochromatosis. Blood 97(12): 3707–12.
  9. 9. Valenti L, Fracanzani AL, Dongiovanni P, Santorelli G, Branchi A, et al. (2002) Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease. Gastroenterology 122(2): 274–80.
  10. 10. Abraham LJ, Kroeger KM (1999) Impact of the −308 TNF promoter polymorphism on the transcriptional regulation of the TNF gene: relevance to disease. J Leukoc Biol 66(4): 562–6.
  11. 11. Bayley JP, Ottenhoff TH, Verweij CL (2004) Is there a future for TNF promoter polymorphisms? Genes Immun 5(5): 315–29.
  12. 12. Badano I, Stietz SM, Schurr TG, Picconi AM, Fekete D, et al. (2012) Analysis of TNFalpha promoter SNPs and the risk of cervical cancer in urban populations of Posadas (Misiones, Argentina). J Clin Virol 53(1): 54–9.
  13. 13. Barbisan G, Perez LO, Contreras A, Golijow CD (2012) TNF-alpha and IL-10 promoter polymorphisms, HPV infection, and cervical cancer risk. Tumour Biol 33(5): 1549–56.
  14. 14. Calhoun ES, McGovern RM, Janney CA, Cerhan JR, Iturria SJ, et al. (2002) Host genetic polymorphism analysis in cervical cancer. Clin Chem 48(8): 1218–24.
  15. 15. Deshpande A, Nolan JP, White PS, Valdez YE, Hunt WC, et al. (2005) TNF-alpha promoter polymorphisms and susceptibility to human papillomavirus 16-associated cervical cancer. J Infect Dis 191(6): 969–76.
  16. 16. Fernandes AP, Goncalves MA, Simoes RT, Mendes-Junior CT, Duarte G, et al. (2008) A pilot case-control association study of cytokine polymorphisms in Brazilian women presenting with HPV-related cervical lesions. Eur J Obstet Gynecol Reprod Biol 140(2): 241–4.
  17. 17. Gostout BS, Poland GA, Calhoun ES, Sohni YR, Giuntoli RL 2nd, et al. (2003) TAP1, TAP2, and HLA-DR2 alleles are predictors of cervical cancer risk. Gynecol Oncol 88(3): 326–32.
  18. 18. Govan VA, Constant D, Hoffman M, Williamson AL (2006) The allelic distribution of −308 Tumor Necrosis Factor-alpha gene polymorphism in South African women with cervical cancer and control women. BMC Cancer 6: 24.
  19. 19. Ivansson EL, Juko-Pecirep I, Gyllensten UB (2010) Interaction of immunological genes on chromosome 2q33 and IFNG in susceptibility to cervical cancer. Gynecol Oncol 116(3): 544–8.
  20. 20. Jang WH, Yang YI, Yea SS, Lee YJ, Chun JH, et al. (2001) The −238 tumor necrosis factor-alpha promoter polymorphism is associated with decreased susceptibility to cancers. Cancer Lett 166(1): 41–6.
  21. 21. Kohaar I, Thakur N, Salhan S, Batra S, Singh V, et al. (2007) TNFalpha-308G/A polymorphism as a risk factor for HPV associated cervical cancer in Indian population. Cell Oncol 29(3): 249–56.
  22. 22. Stanczuk GA, Sibanda EN, Tswana SA, Bergstrom S (2003) Polymorphism at the −308-promoter position of the tumor necrosis factor-alpha (TNF-alpha) gene and cervical cancer. Int J Gynecol Cancer 13(2): 148–53.
  23. 23. Wang N, Yin D, Zhang S, Wei H, Wang S, et al. (2012) TNF-alpha rs1800629 polymorphism is not associated with HPV infection or cervical cancer in the Chinese population. PLoS One 7(9): e45246.
  24. 24. Wang Q, Zhang C, Walayat S, Chen HW, Wang Y (2011) Association between cytokine gene polymorphisms and cervical cancer in a Chinese population. Eur J Obstet Gynecol Reprod Biol 158(2): 330–3.
  25. 25. Wang SS, Bratti MC, Rodriguez AC, Herrero R, Burk RD, et al. (2009) Common variants in immune and DNA repair genes and risk for human papillomavirus persistence and progression to cervical cancer. J Infect Dis 199(1): 20–30.
  26. 26. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414): 557–60.
  27. 27. Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22(4): 719–48.
  28. 28. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3): 177–88.
  29. 29. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109): 629–34.
  30. 30. Duarte I, Santos A, Sousa H, Catarino R, Pinto D, et al. (2005) G-308A TNF-alpha polymorphism is associated with an increased risk of invasive cervical cancer. Biochem Biophys Res Commun 334(2): 588–92.
  31. 31. Huang LL, Xu LF (2012) Research of gene polymorphism of cytokines on human papilloma virus induced cervical injury [Article in Chinese]. JOURNAL OF BENGBU MEDICAL COLLEGE 37(7): 783–7.
  32. 32. Nieves-Ramirez ME, Partida-Rodriguez O, Alegre-Crespo PE, Tapia-Lugo Mdel C, Perez-Rodriguez ME (2011) Characterization of Single-Nucleotide Polymorphisms in the Tumor Necrosis Factor alpha Promoter Region and in Lymphotoxin alpha in Squamous Intraepithelial Lesions, Precursors of Cervical Cancer. Transl Oncol 4(6): 336–44.
  33. 33. Singh H, Jain M, Sachan R, Mittal B (2009) Association of TNFA (−308G>A) and IL-10 (−819C>T) promoter polymorphisms with risk of cervical cancer. Int J Gynecol Cancer 19(7): 1190–4.
  34. 34. Zu FY, Ai XZ, La L, Wu S, Gu ZL (2010) A preliminary study of TNFα gene 308 single nucleotide polymorphism with cervical cancer risk and HPV subtype infection in southern Xinjiang Uygur patients [Article in Chinese]. CHINESE JOURNAL OF OBSTETRICS AND GYNECOLOGY 45(9): 709–11.
  35. 35. Ghaderi M, Nikitina L, Peacock CS, Hjelmstrom P, Hallmans G, et al. (2000) Tumor necrosis factor a-11 and DR15-DQ6 (B*0602) haplotype increase the risk for cervical intraepithelial neoplasia in human papillomavirus 16 seropositive women in Northern Sweden. Cancer Epidemiol Biomarkers Prev 9(10): 1067–70.
  36. 36. Ghaderi M, Nikitina Zake L, Wallin K, Wiklund F, Hallmans G, et al. (2001) Tumor necrosis factor A and MHC class I chain related gene A (MIC-A) polymorphisms in Swedish patients with cervical cancer. Hum Immunol 62(10): 1153–8.
  37. 37. Ivansson EL, Magnusson JJ, Magnusson PK, Erlich HA, Gyllensten UB (2008) MHC loci affecting cervical cancer risk: distinguishing the effects of HLA-DQB1 and non-HLA genes TNF, LTA, TAP1 and TAP2. Genes Immun 9(7): 613–23.
  38. 38. Kirkpatrick A, Bidwell J, van den Brule AJ, Meijer CJ, Pawade J, et al. (2004) TNFalpha polymorphism frequencies in HPV-associated cervical dysplasia. Gynecol Oncol 92(2): 675–9.
  39. 39. Simoes RT, Goncalves MA, Donadi EA, Simoes AL, Bettini JS, et al. (2005) Association of tumor necrosis factor a-2 and a-8 microsatellite alleles with human papillomavirus and squamous intraepithelial lesions among women in Brazil. J Clin Microbiol 43(8): 3932–7.
  40. 40. Habbous S, Pang V, Eng L, Xu W, Kurtz G, et al. (2012) p53 Arg72Pro polymorphism, HPV status and initiation, progression, and development of cervical cancer: a systematic review and meta-analysis. Clin Cancer Res 18(23): 6407–15.
  41. 41. Long S, Yang X, Liu X, Yang P (2012) Methylenetetrahydrofolate Reductase (MTHFR) Polymorphisms and Susceptibility for Cervical Lesions: A Meta-Analysis. PLoS One 7(12): e52381.
  42. 42. Xia L, Gao J, Liu Y, Wu K (2013) Significant association between CYP1A1 T3801C polymorphism and cervical neoplasia risk: a systematic review and meta-analysis. Tumour Biol 34(1): 223–30.