Email updates

Keep up to date with the latest news and content from Diagnostic Pathology and BioMed Central.

Open Access Highly Accessed Research

Lack of association between a functional polymorphism (rs1800796) in the interleukin-6 gene promoter and lung cancer

Weihua Wang*, Jie Chen, Feng Zhao, Burong Zhang and Hongsheng Yu

Author Affiliations

The Affiliated Hospital of Medical College of Ningbo University, Ningbo 315020 Zhejiang, China

For all author emails, please log on.

Diagnostic Pathology 2014, 9:134  doi:10.1186/1746-1596-9-134

The electronic version of this article is the complete one and can be found online at: http://www.diagnosticpathology.org/content/9/1/134


Received:5 May 2014
Accepted:22 June 2014
Published:1 July 2014

© 2014 Wang et al.; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Abstract

Background

A number of studies have examined the association between interleukin-6 (IL-6) rs1800796 polymorphism and risk of lung cancer but revealed inconsistent results. The aim of this study was to clarify the association between IL-6 rs1800796 polymorphism and risk of lung cancer.

Methods

Literature databases including PubMed, Embase and CNKI were searched up to January 2014. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) under co-dominant model, dominant model and recessive model were estimated using random-effects model.

Results

A total of seven studies, including 2691 lung cancer cases and 3067 controls, were included in the meta-analysis. The results suggested that IL-6 rs1800796 polymorphism was not associated with risk of lung cancer under homogeneous co-dominant model (OR = 1.06, 95%CI = 0.73-1.54), heterogeneous co-dominant model (OR = 1.24, 95%CI = 0.96-1.60), dominant model (OR = 1.23, 95%CI = 0.95-1.58) and recessive model (OR = 0.96, 95%CI = 0.70-1.32). The association was still not significant in either never-smokers (OR = 1.19, 95%CI = 0.95-1.48) or ever-smokers (OR = 1.73, 95%CI = 0.89-3.36).

Conclusion

The present meta-analysis suggested that there was no association between IL-6 rs1800796 polymorphism and lung cancer, which was independent of smoking status.

Virtual Slides

The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1060061508127855 webcite

Keywords:
Interleukin-6; Lung cancer; Polymorphism; Meta-analysis

Background

Lung cancer has become a major public health issue worldwide, which accounts for 13% of the total cancer cases and 18% of total deaths in 2008 [1]. To date, the potential mechanism of lung carcinogenesis is not clear. Although it is established that cigarette smoking is one of the most important risk factors causing lung cancer, only 10–15% of heavy tobacco smokers ultimately develop lung cancer [2]. This evidence suggests that genetic factors may play an important role in the development of lung cancer.

Several studies suggested that chronic inflammation predisposes individuals to different types of cancer, including lung cancer. Interleukin-6 (IL-6) is a major cytokine that is known to affect immune response, which is expressed in tumor-infiltrating cells. IL-6 plays a key role in cell survival, proliferation and apoptosis [3]. Three functional polymorphisms (rs1800795 [-174G > C], rs1800796 [-572C > G or -634C > G] and rs10499563 [-6331 T > C]) associated with IL-6 transcription activity have been identified in the IL-6 promoter region. To date, a great number of studies have investigated the association between IL-6 rs1800795 polymorphism and lung cancer, and two meta-analyses [4,5] demonstrated that IL-6 rs1800795 polymorphism was not associated with risk of lung cancer. In addition, some studies suggested that IL-6 rs1800796 might be associated with risk of lung cancer; however, the results have been inconsistent [6-11]. To our knowledge, no meta-analysis has been performed to address this topic.

Therefore, in the present study, we aimed to perform a meta-analysis to clarify the association between IL-6 rs1800796 polymorphism and risk of lung cancer.

Methods

Literature and search strategy

PubMed, EMBASE, and CNKI databases were searched for eligible publications. We used the following key words to identify the potential studies: (Interleukin-6 OR IL-6) and (variant OR variation OR polymorphism OR genotype) and lung cancer. Publication language was restricted to English or Chinese. We also hand-searched the reference lists of retrieved article. If duplicative publications existed, only the study with the large sample size was included. The last literature search was on January 1, 2014.

Inclusion criteria and data extraction

The inclusion criteria for the studies included: (1) evaluated the association of IL-6 rs1800796 polymorphism with lung cancer; (2) used case–control or cohort design; and (3) provided sufficient data for calculation of odds ratio (OR) with 95% confidence interval (CI). The extracted information from each study included: (1) name of the first author; (2) year of publication; (3) country of origin; (4) sample sizes of cases and controls; (5) genotype distributions of cases and controls; and (6) whether the variant was in Hardy Weinberg Equilibrium (HWE) in controls. Two authors (Weihua Wang and Jie Chen) independently searched articles and extracted the data. The third person was asked if they have different opinions.

Statistical analysis

The association between IL-6 rs1800796 polymorphism and risk of lung cancer was estimated by calculation of pooled OR and 95%CI under a co-dominant, a dominant, and a recessive model, respectively. Z test was used to determine the significance of pooled OR (p < 0.05 was considered statistically significant). The between-study heterogeneity was evaluated by Q test and and I2 statistic [12]. A random- [13] or fixed- [14] effects model was performed to calculate pooled OR in the presence (p ≤ 0.10) or absence (p > 0.10) of heterogeneity, respectively. Subgroup analysis by whether the subjects smoke was performed. Begg’s test [15] was performed to assess publication bias (p < 0.05 was considered statistically significant). STATA version 11 (StataCorp LP, College Station, TX, USA) was applied to perform data analysis.

Results

Characteristics of the studies

After literature search, a total of 87 publications were identified. 67 articles were excluded because of obvious irrelevance after reading abstract or title. In addition, two reviews, two articles on meta-analysis of other polymorphisms and eight articles on other polymorphisms were excluded. Then, one article not in HWE [16] and one duplicated publication [17] were further excluded. At last, a total of seven studies from six publications were included in the meta-analysis (Figure 1). Of seven studies, five were conducted in China, one was conducted in Singapore, and one was conducted in Japan. All study populations were East Asians. The polymorphism in all the included studies was in HWE in controls (all P > 0.05). The characteristics of all the included studies are listed in Table 1.

thumbnailFigure 1. Flowchart of study selection.

Table 1. Characteristics of the included studies of the association between IL-6 rs1800796 variant and lung cancer

Meta-analysis results

A total of 2691 cases with lung cancer and 3067 normal controls were included in the meta-analysis. The results suggested that IL-6 rs1800796 polymorphism was not associated with risk of lung cancer under homogeneous co-dominant model (OR = 1.06, 95%CI = 0.73-1.54, Figure 2), heterogeneous co-dominant model (OR = 1.24, 95%CI = 0.96-1.60, Figure 3), dominant model (OR = 1.23, 95%CI = 0.95-1.58, Figure 4), recessive model (OR = 0.96, 95%CI = 0.70-1.32, Figure 5) and allelic model (OR = 1.15, 95%CI = 0.95-1.41, Figure 6). Besides using raw genotype data, we also pooled the results adjusted for most common confounding factors under co-dominant model. The non-significant association did not change (homogeneous co-dominant model: OR = 0.94, 95%CI = 0.78-1.14; heterogeneous co-dominant model: OR = 1.21, 95%CI = 0.92-1.59).

thumbnailFigure 2. Forest plot of the association between IL-6 rs1800796 variant and lung cancer under homogeneous co-dominant model (CC vs. GG).

thumbnailFigure 3. Forest plot of the association between IL-6 rs1800796 variant and lung cancer under heterogeneous co-dominant model (GC vs. GG).

thumbnailFigure 4. Forest plot of the association between IL-6 rs1800796 variant and lung cancer under dominant model (CC + GC vs. GG).

thumbnailFigure 5. Forest plot of the association between IL-6 rs1800796 variant and lung cancer under recessive model (CC vs. GG + GC).

thumbnailFigure 6. Forest plot of the association between IL-6 rs1800796 variant and lung cancer under allelic model (C vs. G).

Cigarette smoking is a most important risk factor for lung cancer, and it may modify the association between IL-6 rs1800796 polymorphism and risk of lung cancer, the subgroup analysis stratified by smoking status (no vs. yes) was performed. However, the association was still not significant in either never-smokers (OR = 1.19, 95%CI = 0.95-1.48, Additional file 1: Figure S1) or ever-smokers (OR = 1.73, 95%CI = 0.89-3.36, Additional file 2: Figure S2).

Additional file 1. Forest plot of the association between IL-6 rs1800796 variant and lung cancer in never-smokers with adjustment for potential confounders (dominant model: CC+GC vs. GG).

Format: DOC Size: 732KB Download file

This file can be viewed with: Microsoft Word ViewerOpen Data

Additional file 2. Forest plot of the association between IL-6 rs1800796 variant and lung cancer in smokers with adjustment for potential confounders (dominant model: CC+GC vs. GG).

Format: DOC Size: 751KB Download file

This file can be viewed with: Microsoft Word ViewerOpen Data

Since there was significant between-study heterogeneity for association between IL-6 rs1800796 polymorphism and risk of lung cancer under all genetic models, we performed a meta-regression analysis to explore source of heterogeneity. We introduced variables including publication year, genotype methods, sample size in cases and controls. However, these variables cannot explain the source of heterogeneity.

Potential publication bias

No publication bias was detected for association between IL-6 rs1800796 polymorphism and risk of lung cancer under all genetic models using the Begg’s test (P = 0.133 for homogeneous co-dominant model; P = 0.230 for heterogeneous co-dominant model; P = 0.230 for dominant model; P = 0.230 for recessive model; P = 0.368 for allelic model).

Discussion

The present meta-analysis demonstrated that IL-6 rs1800796 polymorphism was not associated with risk of lung cancer under all genetic models. In the subgroup analysis, the non-significant association remained in either never-smokers or smokers.

A previous meta-analysis reported that there was no significant association between IL-6 level and lung cancer risk [18]. However, higher level of IL-6 is suggested to be associated with risk of coronary heart disease [19] and type 2 diabetes [20]. In regards to the functional polymorphism rs1800796 in the IL-6 gene, it was only found to be associated with risk of type 2 diabetes [21], but not with coronary heart disease [22].

It is consistent that rs1800795 polymorphism was not associated nearly all types of cancers, including colorectal [23], prostate [24], gastric [25] and breast cancers [26]. But rs1800796 polymorphism was found to be associated with prostate [24] cancer but not with gastric cancer [25]. Based on 2691 cases with lung cancer and 3067 normal controls, we did find significant association between rs1800796 polymorphism and lung cancer.

Heterogeneity may potentially affect the interpretation of the results. Heterogeneity may be attributed to the potential confounding resulted from publication time, sample sizes, measurement errors, or the interaction with other risk factors. In our study, there was significant between-study heterogeneity for association between IL-6 rs1800796 polymorphism and risk of lung cancer under all genetic models. However, meta-regression analysis in consideration of the potential confounders did not address the heterogeneity.

There are several limitations in the present study. First, there might be effects of gene–gene and gene–environment interactions [27-29] but we can not address this because the individual studies did not provide the related data. Second, the sample size in the subgroups was limited and the results should be interpreted with caution. Third, we only assessed one polymorphism in the IL-6 gene, therefore, we can not rule out the possibility that other polymorphisms or haplotypes in this gene might be implicated in the development of lung cancer. Fourth, all the six papers we selected were from East Asia. Thus, the conclusion should not be generalized to other ethnic populations.

Conclusions

In conclusions, the results of our meta-analysis indicated that there was no significant association between IL-6 rs1800796 polymorphism and risk of lung cancer, and the non-significant association was independent of whether the individuals smoked cigarettes.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

WW and JC designed the study and drafted the manuscript. JC and FZ searched the databases and extracted the data. BZ and HY performed the statistical analysis. All authors read, revised and approved the final manuscript.

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics.

    CA Cancer J Clin 2011, 61:69-90. OpenURL

  2. Toh CK, Gao F, Lim WT, Leong SS, Fong KW, Yap SP, Hsu AA, Eng P, Koong HN, Thirugnanam A, Tan EH: Never-smokers with lung cancer: epidemiologic evidence of a distinct disease entity.

    J Clin Oncol 2006, 24:2245-2251. OpenURL

  3. Kishimoto T: Interleukin-6: from basic science to medicine–40 years in immunology.

    Annu Rev Immunol 2005, 23:1-21. OpenURL

  4. Xu B, Niu XB, Wang ZD, Cheng W, Tong N, Mi YY, Min ZC, Tao J, Li PC, Zhang W, Wu HF, Zhang ZD, Wang ZJ, Hua LX, Feng NH, Wang XR: IL-6–174G > C polymorphism and cancer risk: a meta-analysis involving 29,377 cases and 37,739 controls.

    Mol Biol Rep 2011, 38:2589-2596. OpenURL

  5. Peng WJ, He Q, Yang JX, Wang BX, Lu MM, Wang S, Wang J: Meta-analysis of association between cytokine gene polymorphisms and lung cancer risk.

    Mol Biol Rep 2012, 39:5187-5194. OpenURL

  6. Su M: Interleukin 6–634 and interleukin 1β-31 gene polymorphisms and lung cancer risk in female non-smokers.

    Master Dissertation of Chinese Medical Sciences University. 2011.

    in Chinese

    OpenURL

  7. Lim WY, Chen Y, Ali SM, Chuah KL, Eng P, Leong SS, Lim E, Lim TK, Ng AW, Poh WT, Tee A, Teh M, Salim A, Seow A: Polymorphisms in inflammatory pathway genes, host factors and lung cancer risk in Chinese female never-smokers.

    Carcinogenesis 2011, 32:522-529. OpenURL

  8. Bai L, Yu H, Wang H, Su H, Zhao J, Zhao Y: Genetic single-nucleotide polymorphisms of inflammation-related factors associated with risk of lung cancer.

    Med Oncol 2013, 30:414. OpenURL

  9. Chen J, Liu RY, Yang L, Zhao J, Zhao X, Lu D, Yi N, Han B, Chen XF, Zhang K, He J, Lei Z, Zhou Y, Pasche B, Li X, Zhang HT: A two-SNP IL-6 promoter haplotype is associated with increased lung cancer risk.

    J Cancer Res Clin Oncol 2013, 139:231-242. OpenURL

  10. Liang J, Liu X, Bi Z, Yin B, Xiao J, Liu H, Li Y: Relationship between gene polymorphisms of two cytokine genes (TNF-α and IL-6) and occurring of lung cancers in the ethnic group Han of China.

    Mol Biol Rep 2013, 40:1541-1546. OpenURL

  11. Kiyohara C, Horiuchi T, Takayama K, Nakanishi Y: Genetic polymorphisms involved in the inflammatory response and lung cancer risk: A case–control study in Japan.

    Cytokine 2014, 65:88-94. OpenURL

  12. Higgins JP, Thompson SG, Deeks JJ, Altman DG: Measuring inconsistency in meta-analyses.

    BMJ 2003, 327:557-560. OpenURL

  13. DerSimonian R, Laird N: Meta-analysis in clinical trials.

    Control Clin Trials 1986, 7:177-188. OpenURL

  14. Mantel N, Haenszel W: Statistical aspects of the analysis of data from retrospective studies of disease.

    J Natl Cancer Inst 1959, 22:719-748. OpenURL

  15. Begg CB, Mazumdar M: Operating characteristics of a rank correlation test for publication bias.

    Biometrics 1994, 50:1088-1101. OpenURL

  16. Liu X, Li Y, Liang J, Sun D, Dai Y, Cao B: The associaiton of interleukin-6 gene polymorphism and lung cancer.

    Chin J Clin Oncol 2007, 34:562-565.

    (in Chinese)

    OpenURL

  17. Seow A, Ng DP, Choo S, Eng P, Poh WT, Ming T, Wang YT: Joint effect of asthma/atopy and an IL-6 gene polymorphism on lung cancer risk among lifetime non-smoking Chinese women.

    Carcinogenesis 2006, 27:1240-1244. OpenURL

  18. Zhou B, Liu J, Wang ZM, Xi T: C-reactive protein, interleukin 6 and lung cancer risk: a meta-analysis.

    PLoS One 2012, 7:e43075. OpenURL

  19. Kaptoge S, Seshasai SR, Gao P, Freitag DF, Butterworth AS, Borglykke A, Di Angelantonio E, Gudnason V, Rumley A, Lowe GD, Jørgensen T, Danesh J: Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis.

    Eur Heart J 2014, 35:578-589. OpenURL

  20. Wang X, Bao W, Liu J, Ouyang YY, Wang D, Rong S, Xiao X, Shan ZL, Zhang Y, Yao P, Liu LG: Inflammatory markers and risk of type 2 diabetes: a systematic review and meta-analysis.

    Diabetes Care 2013, 36:166-175. OpenURL

  21. Yin YW, Sun QQ, Zhang BB, Hu AM, Liu HL, Wang Q, Zeng YH, Xu RJ, Zhang ZD, Zhang ZG: Association between the interleukin-6 gene -572 C/G polymorphism and the risk of type 2 diabetes mellitus: a meta-analysis of 11,681 subjects.

    Ann Hum Genet 2013, 77:106-114. OpenURL

  22. Zheng GH, Chen HY, Xiong SQ: Polymorphisms of -174G > C and -572G > C in the interleukin 6 (IL-6) gene and coronary heart disease risk: a meta-analysis of 27 research studies.

    PLoS One 2012, 7:e34839. OpenURL

  23. Hu JJ, Wang ZT, Zhong J: Lack of association between the interleukin 6 gene -174G > C polymorphism and colorectal cancer: evidence from a meta-analysis.

    Genet Mol Res 2013, 12:2205-2214. OpenURL

  24. Magalhães JF, Cortinhas AJ, Albuquerque CM, Baptista CS, Ribeiro R, Viegas C, Matos A, Machado J, Pires MA, Guedes-Pinto H, Martins-Bessa A, Leitão JC, Bastos E: Interleukin-6 gene -174G > C and -636G > C promoter polymorphisms and prostate cancer risk.

    Mol Biol Rep 2013, 40:449-455. OpenURL

  25. Yin YW, Sun QQ, Hu AM, Wang Q, Liu HL, Hou ZZ, Zeng YH, Xu RJ, Shi LB, Ma JB: Associations between interleukin-6 gene -174 C/G and -572 C/G polymorphisms and the risk of gastric cancer: a meta-analysis.

    J Surg Oncol 2012, 106:987-993. OpenURL

  26. Yu KD, Di GH, Fan L, Chen AX, Yang C, Shao ZM: Lack of an association between a functional polymorphism in the interleukin-6 gene promoter and breast cancer risk: a meta-analysis involving 25,703 subjects.

    Breast Cancer Res Treat 2010, 122:483-488. OpenURL

  27. Ma L, Zhao J, Li T, He Y, Wang J, Xie L, Qin X1, Li S: Association between Tumor necrosis factor-alpha gene polymorphisms and prostate cancer risk: a meta-analysis.

    Diagn Pathol 2014, 9:74. OpenURL

  28. Liu Y, Tang W, Wang J, Xie L, Li T, He Y, Qin X, Li S: Clinicopathological and prognostic significance of S100A4 overexpression in colorectal cancer: a meta-analysis.

    Diagn Pathol 2013, 8:181. OpenURL

  29. Xu Z, Yu L, Zhang X: Association between the hOGG1 Ser326Cys polymorphism and lung cancer susceptibility: a meta-analysis based on 22,475 subjects.

    Diagn Pathol 2013, 8:144. OpenURL