Inflammation Research

, Volume 61, Issue 7, pp 665–671 | Cite as

The association between interleukin-6 polymorphisms and rheumatoid arthritis: a meta-analysis

  • Young Ho Lee
  • Sang-Cheol Bae
  • Sung Jae Choi
  • Jong Dae Ji
  • Gwan Gyu Song
Original Research Paper



The aim of this study was to determine whether the functional interleukin-6 (IL-6) promoter −174 G/C and −572 G/C polymorphisms confer susceptibility to rheumatoid arthritis (RA) in ethnically different populations.


Meta-analysis was conducted on the associations between these IL-6 polymorphisms and RA.


A total of nine studies involving 3,851 subjects (RA 2,053 and controls 1,798) were considered in this study and ethnicity-specific meta-analysis was performed on European subjects. In all study subjects, meta-analysis revealed a trend toward to an association between RA and the IL-6 −174 G allele (odds ratio [OR] = 0.699, 95 % confidence interval [CI] = 0.463–1.054, p = 0.088). Stratification by ethnicity indicated a significant association between RA and the IL-6 −174 G/C polymorphism in Europeans using the dominant (OR = 0.329, 95 % CI = 0.155–0.699, p = 0.004) and recessive (OR = 0.823, 95 % CI = 0.679–0.997, p = 0.047) models. Meta-analysis of the IL-6 −572 G/C polymorphism showed no association between RA and the IL-6 −572 G allele in all study subjects (OR = 1.641, 95 % CI = 0.613–4.397, p = 0.324).


This meta-analysis shows that the IL-6 −174 G/C polymorphism may confer susceptibility to RA in Europeans.


Interleukin-6 Polymorphism Rheumatoid arthritis Meta-analysis 



This study is supported by a grant from the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A102065).

Conflict of interest

The authors have no financial and non-financial conflicts of interest to declare.


  1. 1.
    Choi SJ, Rho YH, Ji JD, Song GG, Lee YH. Genome scan meta-analysis of rheumatoid arthritis. Rheumatology (Oxford). 2006;45:166–70.CrossRefGoogle Scholar
  2. 2.
    Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447:661-678.Google Scholar
  3. 3.
    Fonseca JE, Santos MJ, Canhao H, Choy E. Interleukin-6 as a key player in systemic inflammation and joint destruction. Autoimmun Rev. 2009;8:538–42.PubMedCrossRefGoogle Scholar
  4. 4.
    Nurnberg W, Haas N, Schadendorf D, Czarnetzki BM. Interleukin-6 expression in the skin of patients with lupus erythematosus. Exp Dermatol. 1995;4:52–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Emery P, Keystone E, Tony HP, Cantagrel A, van Vollenhoven R, Sanchez A, Alecock E, Lee J, Kremer J. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008;67:1516–23.PubMedCrossRefGoogle Scholar
  6. 6.
    Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S, Woo P. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest. 1998;102:1369–76.PubMedCrossRefGoogle Scholar
  7. 7.
    Arman A, Coker A, Sarioz O, Inanc N, Direskeneli H. Lack of association between IL-6 gene polymorphisms and rheumatoid arthritis in Turkish population. Rheumatol Int. 2011 (Epub ahead of print)
  8. 8.
    Palomino-Morales R, Gonzalez-Juanatey C, Vazquez-Rodriguez TR, Miranda-Filloy JA, Llorca J, Martin J, Gonzalez-Gay MA. Interleukin-6 gene −174 promoter polymorphism is associated with endothelial dysfunction but not with disease susceptibility in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2009;27:964–70.PubMedGoogle Scholar
  9. 9.
    Trajkov D, Mishevska-Perchinkova S, Karadzova-Stojanoska A, Petlichkovski A, Strezova A, Spiroski M. Association of 22 cytokine gene polymorphisms with rheumatoid arthritis in population of ethnic Macedonians. Clin Rheumatol. 2009;28:1291–300.PubMedCrossRefGoogle Scholar
  10. 10.
    Panoulas VF, Stavropoulos-Kalinoglou A, Metsios GS, Smith JP, Milionis HJ, Douglas KM, Nightingale P, Kitas GD. Association of interleukin-6 (IL-6) −174G/C gene polymorphism with cardiovascular disease in patients with rheumatoid arthritis: the role of obesity and smoking. Atherosclerosis. 2009;204:178–83.PubMedCrossRefGoogle Scholar
  11. 11.
    Huang XZ, Zhuang JH, Ren YG, Zhou LJ, Zhou Q. Association of interleukin-6 and interleukin-18 gene polymorphism with rheumatoid arthritis in Guangdong Han population. Nan Fang Yi Ke Da Xue Xue Bao. 2007;27:1661–4.PubMedGoogle Scholar
  12. 12.
    Pawlik A, Wrzesniewska J, Florczak M, Gawronska-Szklarz B, Herczynska M. IL-6 promoter polymorphism in patients with rheumatoid arthritis. Scand J Rheumatol. 2005;34:109–13.PubMedCrossRefGoogle Scholar
  13. 13.
    Martinez A, Pascual M, Pascual-Salcedo D, Balsa A, Martin J, de la Concha EG. Genetic polymorphisms in Spanish rheumatoid arthritis patients: an association and linkage study. Genes Immun. 2003;4:117–21.PubMedCrossRefGoogle Scholar
  14. 14.
    Crilly A, Bartlett JM, White A, Stirling D, Capell H, Madhok R. Investigation of novel polymorphisms within the 3′ region of the IL-6 gene in patients with rheumatoid arthritis using Genescan analysis. Cytokine. 2001;13:109–12.PubMedCrossRefGoogle Scholar
  15. 15.
    Fugger L, Morling N, Bendtzen K, Ryder L, Andersen V, Heilman C, Karup Pedersen F, Friis J, Halbert P, Svejgaard A. IL-6 gene polymorphism in rheumatoid arthritis, pauciarticular juvenile rheumatoid arthritis, systemic lupus erythematosus, and in healthy Danes. J Immunogenet. 1989;16:461–5.PubMedCrossRefGoogle Scholar
  16. 16.
    Lee YH, Rho YH, Choi SJ, Ji JD, Song GG, Nath SK, Harley JB. The PTPN22 C1858T functional polymorphism and autoimmune diseases—a meta-analysis. Rheumatology (Oxford). 2007;46:49–56.CrossRefGoogle Scholar
  17. 17.
    Lee YH, Harley JB, Nath SK. Meta-analysis of TNF-alpha promoter -308 A/G polymorphism and SLE susceptibility. Eur J Hum Genet. 2006;14:364–71.PubMedCrossRefGoogle Scholar
  18. 18.
    Lee YH, Rho YH, Choi SJ, Ji JD, Song GG. Association of TNF-alpha -308 G/A polymorphism with responsiveness to TNF-alpha-blockers in rheumatoid arthritis: a meta-analysis. Rheumatol Int. 2006;27:157–61.PubMedCrossRefGoogle Scholar
  19. 19.
    Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.PubMedCrossRefGoogle Scholar
  20. 20.
    Davey Smith G, Egger M. Meta-analyses of randomised controlled trials. Lancet. 1997;350:1182.PubMedCrossRefGoogle Scholar
  21. 21.
    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.PubMedCrossRefGoogle Scholar
  22. 22.
    Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.PubMedCrossRefGoogle Scholar
  23. 23.
    Lopez-Mejias R, Garcia-Bermudez M, Gonzalez-Juanatey C, Castaneda S, Perez-Esteban S, Miranda-Filloy JA, Gomez-Vaquero C, Fernandez-Gutierrez B, Balsa A, Pascual-Salcedo D, Blanco R, Gonzalez-Alvaro I, Llorca J, Martin J, Gonzalez-Gay MA. Lack of association between IL6 single nucleotide polymorphisms and cardiovascular disease in Spanish patients with rheumatoid arthritis. Atherosclerosis. 2011;219:655–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Lo SF, Huang CM, Lin HC, Chen WC, Tsai CH, Tsai FJ. Cytokine (IL-6) and chemokine (IL-8) gene polymorphisms among rheumatoid arthritis patients in Taiwan. Clin Exp Rheumatol. 2008;26:632–7.PubMedGoogle Scholar
  25. 25.
    Blankenstein T, Volk HD, Techert-Jendrusch C, Qin ZH, Richter G, Diamantstein T. Lack of correlation between BglII RFLP in the human interleukin 6 gene and rheumatoid arthritis. Nucleic Acids Res. 1989;17:8902.PubMedCrossRefGoogle Scholar
  26. 26.
    Lee YH, Rho YH, Choi SJ, Ji JD, Song GG. PADI4 polymorphisms and rheumatoid arthritis susceptibility: a meta-analysis. Rheumatol Int. 2007;27:827–33.PubMedCrossRefGoogle Scholar
  27. 27.
    Lee YH, Woo JH, Choi SJ, Ji JD, Song GG. Association of programmed cell death 1 polymorphisms and systemic lupus erythematosus: a meta-analysis. Lupus. 2009;18:9–15.PubMedCrossRefGoogle Scholar
  28. 28.
    Lee YH, Bae SC, Choi SJ, Ji JD, Song GG (2011) Association between the CTLA-4 +49 A/G polymorphism and susceptibility to rheumatoid arthritis: a meta-analysis. Mol Biol Rep (Epub ahead of print) doi: 10.1007/s11033-011-1364-3
  29. 29.
    Morse HR, Olomolaiye OO, Wood NA, Keen LJ, Bidwell JL. Induced heteroduplex genotyping of TNF-alpha, IL-1beta, IL-6 and IL-10 polymorphisms associated with transcriptional regulation. Cytokine. 1999;11:789–95.PubMedCrossRefGoogle Scholar
  30. 30.
    Hulkkonen J, Pertovaara M, Antonen J, Pasternack A, Hurme M. Elevated interleukin-6 plasma levels are regulated by the promoter region polymorphism of the IL6 gene in primary Sjogren’s syndrome and correlate with the clinical manifestations of the disease. Rheumatology (Oxford). 2001;40:656–61.CrossRefGoogle Scholar
  31. 31.
    Brull DJ, Montgomery HE, Sanders J, Dhamrait S, Luong L, Rumley A, Lowe GD, Humphries SE. Interleukin-6 gene −174g > c and −572g > c promoter polymorphisms are strong predictors of plasma interleukin-6 levels after coronary artery bypass surgery. Arterioscler Thromb Vasc Biol. 2001;21:1458–63.PubMedCrossRefGoogle Scholar
  32. 32.
    Chen RH, Chang CT, Chen WC, Tsai CH, Tsai FJ. Proinflammatory cytokine gene polymorphisms among Hashimoto’s thyroiditis patients. J Clin Lab Anal. 2006;20:260–5.PubMedCrossRefGoogle Scholar
  33. 33.
    Sie MP, Sayed-Tabatabaei FA, Oei HH, Uitterlinden AG, Pols HA, Hofman A, van Duijn CM, Witteman JC. Interleukin 6–174 g/c promoter polymorphism and risk of coronary heart disease: results from the Rotterdam study and a meta-analysis. Arterioscler Thromb Vasc Biol. 2006;26:212–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Jeon JY, Kim HA, Kim SH, Park HS, Suh CH. Interleukin 6 gene polymorphisms are associated with systemic lupus erythematosus in Koreans. J Rheumatol. 2011;37:2251–8.CrossRefGoogle Scholar
  35. 35.
    Biswas S, Ghoshal PK, Mandal SC, Mandal N. Relation of anti- to pro-inflammatory cytokine ratios with acute myocardial infarction. Korean J Intern Med. 2010;25:44–50.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2012

Authors and Affiliations

  • Young Ho Lee
    • 1
  • Sang-Cheol Bae
    • 2
  • Sung Jae Choi
    • 1
  • Jong Dae Ji
    • 1
  • Gwan Gyu Song
    • 1
  1. 1.Division of Rheumatology, Department of Internal Medicine, Korea University Anam HospitalKorea University College of MedicineSeongbuk-guKorea
  2. 2.The Hospital for Rheumatic DiseasesHanyang University Medical CenterSeoulKorea

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