Digestive Diseases and Sciences

, Volume 56, Issue 8, pp 2227–2236

Polymorphisms of Tumor Necrosis Factor-Alpha and Hepatocellular Carcinoma Risk: A HuGE Systematic Review and Meta-Analysis

  • Yonggang Wei
  • Fei Liu
  • Bo Li
  • Xi Chen
  • Yu Ma
  • Lvnan Yan
  • Tianfu Wen
  • Mingqing Xu
  • Wentao Wang
  • Jiayin Yang
Original Article
  • 425 Downloads

Abstract

Background

Studies investigating the associations between tumor necrosis factor-alpha (TNFA) polymorphisms and hepatocellular carcinoma (HCC) risk report conflicting results. We conducted a meta-analysis to assess the association between TNFA gene TNFA-308(G/A), TNFA-238(G/A), TNFA-863(C/A), TNFA-857(C/T), TNFA-1031 (T/C) polymorphisms and HCC susceptibility.

Methods

Two investigators independently searched the Medline, Embase, CNKI, and Chinese Biomedicine Database. Summary odds ratios (ORs) and 95% confidence intervals (95% CIs) for TNFA polymorphisms and HCC were calculated in a fixed-effects model (the Mantel–Haenszel method) and a random-effects model (the DerSimonian and Laird method) when appropriate.

Results

This meta-analysis included 17 case–control studies, which included 2,357 HCC cases and 3,161 controls. Overall, the variant genotypes AA/AG of -308G/A were associated with a significantly increased HCC risk, when compared with GG genotype (AA vs. GG, OR = 1.97, 95%CI = 1.01–3.83; AG vs. GG, OR = 1.88, 95%CI = 1.23–2.88; AA/AG vs. GG, OR = 1.80, 95%CI = 1.19–2.72). When stratifying for ethnicity, significantly elevated HCC risk was found among Asians. Moreover, similar results were observed between TNFA-238G/A, TNFA-863C/A polymorphisms and HCC risk among Asians (for -238G/A, AG vs. GG OR = 1.63, 95%CI = 1.17–2.26, AA/AG vs. GG OR = 1.61, 95%CI = 1.16–2.24; for -863 C/A, AC vs. CC OR = 1.72, 95%CI = 1.03–2.88, AA/AC vs. CC OR = 1.71, 95%CI = 1.02–2.86), while no associations were observed between TNFA-857C/T, TNFA-1031T/C polymorphisms and HCC susceptibility.

Conclusions

This meta-analysis shows that TNFA-308G/A, TNFA-238G/A and TNFA-863C/A polymorphisms may be associated with HCC among Asians. TNFA-857C/T and TNFA-1031T/C polymorphisms were not detected to be related to the risk for HCC.

Keywords

Hepatocellular carcinoma TNFA Gene polymorphism Meta-analysis 

Abbreviations

HCC

Hepatocellular carcinoma

HBV

Hepatitis B virus

HCV

Hepatitis C virus

OR

Odds ratio

CI

Confidence interval

TNFA

Tumor necrosis factor-alpha

SNPs

Single nucleotide polymorphisms

HWE

Hardy–Weinberg equilibrium

References

  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.PubMedCrossRefGoogle Scholar
  2. 2.
    Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer. 2006;118:3030–3044.PubMedCrossRefGoogle Scholar
  3. 3.
    Michielsen PP, Francque SM, van Dongen JL. Viral hepatitis and hepatocellular carcinoma. World J Surg Oncol. 2005;3:27.PubMedCrossRefGoogle Scholar
  4. 4.
    Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology. 2008;48:1312–1327.PubMedCrossRefGoogle Scholar
  5. 5.
    Takano S, Yokosuka O, Imazeki F, Tagawa M, Omata M. Incidence of hepatocellular carcinoma in chronic hepatitis B and C: A prospective study of 251 patients. Hepatology. 1995;21:650–655.PubMedCrossRefGoogle Scholar
  6. 6.
    Tarao K, Rino Y, Ohkawa S, et al. Association between high serum alanine aminotransferase levels and more rapid development and higher rate of incidence of hepatocellular carcinoma in patients with hepatitis C virus-associated cirrhosis. Cancer. 1999;86:589–595.PubMedCrossRefGoogle Scholar
  7. 7.
    Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–867.PubMedCrossRefGoogle Scholar
  8. 8.
    Yoshimura A. Signal transduction of inflammatory cytokines and tumor development. Cancer Sci. 2006;97:439–447.PubMedCrossRefGoogle Scholar
  9. 9.
    Hajeer AH, Hutchinson IV. Influence of TNF alpha gene polymorphisms on TNF alpha production and disease. Hum Immunol. 2001;62:1191–1199.PubMedCrossRefGoogle Scholar
  10. 10.
    Hajeer AH, Hutchinson IV. TNF-alpha gene polymorphism: Clinical and biological implications. Microsc Res Tech. 2000;50:216–228.PubMedCrossRefGoogle Scholar
  11. 11.
    Anderson GM, Nakada MT, DeWitte M. Tumor necrosis factor-alpha in the pathogenesis and treatment of cancer. Curr Opin Pharmacol. 2004;4:314–320.PubMedCrossRefGoogle Scholar
  12. 12.
    Kroeger KM, Carville KS, Abraham LJ. The -308 tumor necrosis factor-alpha promoter polymorphism effects transcription. Mol Immunol. 1997;34:391–399.PubMedCrossRefGoogle Scholar
  13. 13.
    Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW. Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci USA. 1997;94:3195–3199.PubMedCrossRefGoogle Scholar
  14. 14.
    Wilson AG, di Giovine FS, Blakemore AI, Duff GW. Single base polymorphism in the human tumour necrosis factor alpha (TNF alpha) gene detectable by NcoI restriction of PCR product. Hum Mol Genet. 1992;1:353.PubMedCrossRefGoogle Scholar
  15. 15.
    Higuchi T, Seki N, Kamizono S, et al. Polymorphism of the 5’-flanking region of the human tumor necrosis factor (TNF)-alpha gene in Japanese. Tissue Antigens. 1998;51:605–612.PubMedCrossRefGoogle Scholar
  16. 16.
    Soga Y, Nishimura F, Ohyama H, Maeda H, Takashiba S, Murayama Y. Tumor necrosis factor-alpha gene (TNF-alpha)-1031/-863, -857 single-nucleotide polymorphisms (SNPs) are associated with severe adult periodontitis in Japanese. J Clin Periodontol. 2003;30:524–531.PubMedCrossRefGoogle Scholar
  17. 17.
    Kaijzel EL, Bayley JP, van Krugten MV, et al. Allele-specific quantification of tumor necrosis factor alpha (TNF) transcription and the role of promoter polymorphisms in rheumatoid arthritis patients and healthy individuals. Genes Immun. 2001;2:135–144.PubMedCrossRefGoogle Scholar
  18. 18.
    Uglialoro AM, Turbay D, Pesavento PA, et al. Identification of three new single nucleotide polymorphisms in the human tumor necrosis factor-alpha gene promoter. Tissue Antigens. 1998;52:359–367.PubMedCrossRefGoogle Scholar
  19. 19.
    Mestiri S, Bouaouina N, Ahmed SB, et al. Genetic variation in the tumor necrosis factor-a promoter region and in the stress protein hsp70–2: Susceptibility and prognostic implications in breast carcinoma. Cancer. 2001;91:672–678.PubMedCrossRefGoogle Scholar
  20. 20.
    Warzocha K, Ribeiro P, Bienvenu J, et al. Genetic polymorphisms in the tumor necrosis factor locus influence non-Hodgkin’s lymphoma outcome. Blood. 1998;91:3574–3581.PubMedGoogle Scholar
  21. 21.
    Oh BR, Sasaki M, Perinchery G, et al. Frequent genotype changes at -308, and 488 regions of the tumor necrosis factor-a (TNF-a) gene in patients with prostate cancer. J Urol. 2000;163:1584–1587.PubMedCrossRefGoogle Scholar
  22. 22.
    Sasaki M, Nakajima K, Perinchery G, et al. Frequent genotype changes at -308 of the human tumor necrosis factor-alpha promoter region in human uterine endometrial cancer. Oncol Rep. 2000;7:369–373.PubMedGoogle Scholar
  23. 23.
    Machado JC, Figueiredo C, Canedo P, et al. A proinflammatory genetic profile increases the risk for chronic atrophic gastritis and gastric carcinoma. Gastroenterology. 2003;125:364–371.PubMedCrossRefGoogle Scholar
  24. 24.
    Qin H, Liu B, Shi T, Liu Y, Sun Y, Ma Y. Tumour necrosis factor-alpha polymorphisms and hepatocellular carcinoma: A meta-analysis. J Int Med Res. 2010;38:760–768.PubMedGoogle Scholar
  25. 25.
    Yang Y, Luo C, Feng R, Bi S. The TNF-α, IL-1B and IL-10 polymorphisms and risk for hepatocellular carcinoma: A meta-analysis. J Cancer Res Clin Oncol. 2010; doi:10.1007/s00432-010-0959-8.
  26. 26.
    Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: A proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) group. JAMA. 2000;283:2008–2012.PubMedCrossRefGoogle Scholar
  27. 27.
    White DL, Li D, Nurgalieva Z, El-Serag HB. Genetic variants of glutathione S-transferase as possible risk factors for hepatocellular carcinoma: a HuGE systematic review and meta-analysis. Am J Epidemiol. 2008;167:377–389.PubMedCrossRefGoogle Scholar
  28. 28.
    Petitti DB. Meta-analysis, decision analysis, and cost-effectiveness analysis: Methods for quantitative synthesis in medicine. 2nd ed. New York, NY: Oxford University Press; 2000.Google Scholar
  29. 29.
    Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–1558.PubMedCrossRefGoogle Scholar
  30. 30.
    Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22:719–748.PubMedGoogle Scholar
  31. 31.
    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188.PubMedCrossRefGoogle Scholar
  32. 32.
    Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–1101.PubMedCrossRefGoogle Scholar
  33. 33.
    Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–634.PubMedGoogle Scholar
  34. 34.
    Song SF, Gao YH, Gao YH, Chen SD, Chen SD. Interaction of TNF-α-308 and environmental risk factors in primary liver cancer. J Guangdong Pharm College. 2009;25:196–201. [Article in Chinese].Google Scholar
  35. 35.
    Huang HL, Huang HL, Xie JS, Xie JS, Huang ZS, Zhao QZ. The relationship of polymorphism of tumor necrosis factor-α gene promoter -238G/A with primary hepatic carcinoma in patients. Prog Anat Sci. 2007;13:11–13. [Article in Chinese].Google Scholar
  36. 36.
    Qiu B. Association study of gene polymorphisms and expression of TNF-α, TAP with hepatocellular carcinoma. Available at: http://dlib3.edu.cnki.net/kns50/detail.aspx?QueryID=17&CurRec=1. 2010 June 1 [Article in Chinese].
  37. 37.
    Niro GA, Fontana R, Gioffreda D, et al. Tumor necrosis factor gene polymorphisms and clearance or progression of hepatitis B virus infection. Liver Int. 2005;25:1175–1181.PubMedCrossRefGoogle Scholar
  38. 38.
    Ben-Ari Z, Mor E, Papo O, et al. Cytokine gene polymorphisms in patients infected with hepatitis B virus. Am J Gastroenterol. 2003;98:144–150.PubMedCrossRefGoogle Scholar
  39. 39.
    Jung KW, Ha E, Yu GI, et al. TNF alpha promoter polymorphism is a risk factor for susceptibility in hepatocellular carcinoma in Korean population. Clin Chim Acta. 2009;407:16–19.PubMedCrossRefGoogle Scholar
  40. 40.
    Jeng JE, Tsai HR, Chuang LY, et al. Independent and additive interactive effects among tumor necrosis factor-alpha polymorphisms, substance use habits, and chronic hepatitis B and hepatitis C virus infection on risk for hepatocellular carcinoma. Medicine (Baltimore). 2009;88:349–357.CrossRefGoogle Scholar
  41. 41.
    Akkiz H, Bayram S, Bekar A, et al. G-308A TNF-alpha polymorphism is associated with an increased risk of hepatocellular carcinoma in the Turkish population: Case-control study. Cancer Epidemiol. 2009;33:261–264.PubMedCrossRefGoogle Scholar
  42. 42.
    Ognjanovic S, Yuan JM, Chaptman AK, Fan Y, Yu MC. Genetic polymorphisms in the cytokine genes and risk of hepatocellular carcinoma in low-risk non-Asians of USA. Carcinogenesis. 2009;30:758–762.PubMedCrossRefGoogle Scholar
  43. 43.
    Sakamoto T, Higaki Y, Hara M, et al. Interaction between interleukin-1beta -31T/C gene polymorphism and drinking and smoking habits on the risk of hepatocellular carcinoma among Japanese. Cancer Lett. 2008;271:98–104.PubMedCrossRefGoogle Scholar
  44. 44.
    Kummee P, Tangkijvanich P, Poovorawan Y, Hirankarn N. Association of HLA-DRB1*13 and TNF-alpha gene polymorphisms with clearance of chronic hepatitis B infection and risk of hepatocellular carcinoma in Thai population. J Viral Hepat. 2007;14:841–848.PubMedGoogle Scholar
  45. 45.
    Jeng JE, Tsai JF, Chuang LY, et al. Tumor necrosis factor-alpha 308.2 polymorphism is associated with advanced hepatic fibrosis and higher risk for hepatocellular carcinoma. Neoplasia. 2007;9:987–992.PubMedCrossRefGoogle Scholar
  46. 46.
    Chen CC, Yang SY, Liu CJ, et al. Association of cytokine and DNA repair gene polymorphisms with hepatitis B-related hepatocellular carcinoma. Int J Epidemiol. 2005;34:1310–1318.PubMedCrossRefGoogle Scholar
  47. 47.
    Migita K, Miyazoe S, Maeda Y, et al. Cytokine gene polymorphisms in Japanese patients with hepatitis B virus infection—association between TGF-beta1 polymorphisms and hepatocellular carcinoma. J Hepatol. 2005;42:505–510.PubMedCrossRefGoogle Scholar
  48. 48.
    Ho SY, Wang YJ, Chen HL, et al. Increased risk of developing hepatocellular carcinoma associated with carriage of the TNF2 allele of the -308 tumor necrosis factor-alpha promoter gene. Cancer Causes Control. 2004;15:657–663.PubMedCrossRefGoogle Scholar
  49. 49.
    Heneghan MA, Johnson PJ, Clare M, Ho S, Harrison PM, Donaldson PT. Frequency and nature of cytokine gene polymorphisms in hepatocellular carcinoma in Hong Kong Chinese. Int J Gastrointest Cancer. 2003;34:19–26.PubMedCrossRefGoogle Scholar
  50. 50.
    Wang Y, Kato N, Hoshida Y, et al. Interleukin-1beta gene polymorphisms associated with hepatocellular carcinoma in hepatitis C virus infection. Hepatology. 2003;37:65–71.PubMedCrossRefGoogle Scholar
  51. 51.
    Zhu ZZ, Cong WM. Roles of hepatitis B virus and hepatitis C virus in hepato-carcinogenesis. Zhonghua Ganzangbing Zazhi. 2003;11:574–576.PubMedGoogle Scholar
  52. 52.
    Kuper H, Tzonou A, Kaklamani E, et al. Tobacco smoking, alcohol consumption and their interaction in the causation of hepatocellular carcinoma. Int J Cancer. 2000;85:498–502.PubMedCrossRefGoogle Scholar
  53. 53.
    Chen CJ, Wang LY, Lu SN, et al. Elevated aflatoxin exposure and increased risk of hepatocellular carcinoma. Hepatology. 1996;24:38–42.PubMedCrossRefGoogle Scholar
  54. 54.
    Bowen DG, Walker CM. Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature. 2005;436:946–952.PubMedCrossRefGoogle Scholar
  55. 55.
    El Serag HB, Mason AC. Risk factors for the rising rates of primary liver cancer in the United States. Arch Intern Med. 2000;160:3227–3230.PubMedCrossRefGoogle Scholar
  56. 56.
    Yu MW, Yang SY, Chiu YH, et al. A p53 genetic polymorphism as a modulator of hepatocellular carcinoma risk in relation to chronic liver disease, familial tendency, and cigarette smoking in hepatitis B carriers. Hepatology. 1999;29:697–702.PubMedCrossRefGoogle Scholar
  57. 57.
    Feo F, Frau M, Tomasi ML, et al. Genetic and epigenetic control of molecular alterations in hepatocellular carcinoma. Exp Biol Med (Maywood). 2009;234:726–736.CrossRefGoogle Scholar
  58. 58.
    Dragani TA. Risk of HCC: Genetic heterogeneity and complex genetics. J Hepatol. 2010;52:252–257.PubMedCrossRefGoogle Scholar
  59. 59.
    Ezzikouri S, El Feydi AE, Benazzouz M, et al. Single nucleotide polymorphism in DNMT3B promoter and its association with hepatocellular carcinoma in a Moroccan population. Infect Genet Evol. 2009;9:877–881.PubMedCrossRefGoogle Scholar
  60. 60.
    Kim YJ, Lee HS. Genetic epidemiological study on single nucleotide polymorphisms associated with hepatocellular carcinoma in patients with chronic HBV infection. Korean J Hepatol. 2009;15:7–14.PubMedCrossRefGoogle Scholar
  61. 61.
    Ioannidis JP, Ntzani EE, Trikalinos TA, et al. Replication validity of genetic association studies. Nat Genet. 2001;29:306–309.PubMedCrossRefGoogle Scholar
  62. 62.
    Munafò M. Replication validity of genetic association studies of smoking behavior: What can meta-analytic techniques offer? Nicotine Tob Res. 2004;6:381–382.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Yonggang Wei
    • 1
  • Fei Liu
    • 1
  • Bo Li
    • 1
  • Xi Chen
    • 1
  • Yu Ma
    • 1
  • Lvnan Yan
    • 1
  • Tianfu Wen
    • 1
  • Mingqing Xu
    • 1
  • Wentao Wang
    • 1
  • Jiayin Yang
    • 1
  1. 1.Department of Liver and Vascular SurgeryWest China Hospital, Sichuan UniversityChengduChina

Personalised recommendations