Skip to main content

Advertisement

Log in

TNF-β +252 A>G (rs909253) polymorphism is independently associated with presence of autoantibodies in rheumatoid arthritis patients

  • Original Article
  • Published:
Clinical and Experimental Medicine Aims and scope Submit manuscript

Abstract

The TNF-β +252 A>G (rs909253) polymorphism has been associated with a risk of development of rheumatoid arthritis (RA) and could influence plasma tumor necrosis factor alpha (TNF-α) levels. The aim of the present study was to evaluate the association between the TNF-β +252 A>G polymorphism with plasma TNF-α levels, the presence of autoantibodies, and the susceptibility for RA. This cross-sectional study included 261 patients with RA and 292 controls. The polymorphism was studied using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). Soluble TNF-α and receptors swere measured by multiplex assay. Rheumatoid factor (RF) and anticyclic citrullinated peptide antibodies (anti-CCP) were measured using immunoassay. No differences were observed in allele frequency and genotype distribution among patients and controls. The presence of RF (p = 0.020) and anti-CCP (p = 0.001) increased 4.23-fold and 8.13-fold, respectively, in patients with B1 allele (B1/B2 + B1/B1 genotypes) independently of demographic, clinical, and inflammatory markers. Among patients with B1/B2 + B1/B1 genotypes, higher TNF-α levels were associated with positive RF (p = 0.040), anti-CCP (p = 0.011), or both (p = 0.038). In patients carrying B1 allele, the increased sTNFR1 together with RF or anti-CCP or both explained about 39.0% the variations in TNF-α level. However, in B2/B2 genotype, the presence of those autoantibodies was not associated with TNF-α level. Our findings indicate that the TNF-β +252 A>G polymorphism was not associated with RA susceptibility and TNF-α plasma levels. However, B1 allele was associated with the presence of autoantibodies. In addition, interaction between the presence of B1 allele and autoantibodies was associated with the increase of plasma TNF-α level in RA patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

ANOVA:

Analysis of variance

anti-CCP:

Anticyclic citrullinated peptide antibodies

CRP:

C-reactive protein

EDTA:

Ethylenediaminetetraacetic acid

ESR:

Erythrocyte sedimentation rate

hsCRP:

High-sensitivity C-reactive protein

HLA:

Human leukocyte antigen

IL:

Interleukin

Ln:

Natural logarithmic

LTA:

Lymphotoxin A

n :

Number

PCR:

Polymerase chain reaction

RA:

Rheumatoid arthritis

RF:

Rheumatoid factor

SEM:

Standard of main

sTNFR-1:

Soluble TNF receptor 1

sTNFR-2:

Soluble TNF receptor 2

TNFR1:

Tumor necrosis factor receptor 1

TNFR2:

Tumor necrosis factor receptor 2

TNF-α:

Tumor necrosis factor-alpha

TNF-β:

Tumor necrosis factor-β

References

  1. Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet. 2010;376:1094–108.

    Article  PubMed  Google Scholar 

  2. Isaacs JD. The changing face of rheumatoid arthritis: sustained remission for all? Nat Rev Immunol. 2010;10:605–11.

    Article  CAS  PubMed  Google Scholar 

  3. Li S, Yu Y, Yue Y, Zhang Z, Su K. Microbial infection and rheumatoid arthritis. J Clin Cell Immunol. 2013;4:174.

    PubMed  PubMed Central  Google Scholar 

  4. Weyand CM, Goronzy JJ. Association of MHC and rheumatoid arthritis: HLA polymorphisms in phenotypic variants of rheumatoid arthritis. Arthritis Res. 2000;2:212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Saad MN, Mabrouk MS, Eldeib AM, Shaker OG. Identification of rheumatoid arthritis biomarkers based on single nucleotide polymorphisms and haplotype blocks: a systematic review and meta-analysis. J Adv Res. 2016;7:1–16.

    Article  CAS  PubMed  Google Scholar 

  6. Sun J, Zhang Y, Liu L, Liu G. Diagnostic accuracy of combined tests of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis: a meta-analysis. Clin Exp Rheumatol. 2014;32:11–21.

    PubMed  Google Scholar 

  7. Nishimura K, Sugiyama D, Kogata Y, et al. Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med. 2007;146:797–808.

    Article  PubMed  Google Scholar 

  8. Aletaha D, Alasti F, Smolen JS. Rheumatoid factor determines structural progression of rheumatoid arthritis dependent and independent of disease activity. Ann Rheum Dis. 2013;72:875–80.

    Article  PubMed  Google Scholar 

  9. Forslind K, Ahlmén M, Eberhardt K, Hafström I, Svensson B. Prediction of radiological outcome in early rheumatoid arthritis in clinical practice: role of antibodies to citrullinated peptides (anti-CCP). Ann Rheum Dis. 2004;63:1090–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rönnelid J, Wick MC, Lampa J, et al. Longitudinal analysis of citrullinated protein/peptide antibodies (anti-CP) during 5 year follow up in early rheumatoid arthritis: anti-CP status predicts worse disease activity and greater radiological progression. Ann Rheum Dis. 2005;64:1744–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Laurent L, Anquetil F, Clavel C, et al. IgM rheumatoid factor amplifies the inflammatory response of macrophages induced by the rheumatoid arthritis-specific immune complexes containing anticitrullinated protein antibodies. Ann Rheum Dis. 2015;74:1425–31.

    Article  CAS  PubMed  Google Scholar 

  12. Clavel C, Nogueira L, Laurent L, et al. Induction of macrophage secretion of tumor necrosis factor α through Fcγ receptor IIa engagement by rheumatoid arthritis-specific autoantibodies to citrullinated proteins complexed with fibrinogen. Arthritis Rheum. 2008;58:678–88.

    Article  CAS  PubMed  Google Scholar 

  13. Sokolove J, Johnson DS, Lahey LJ, et al. Rheumatoid factor as a potentiator of anti-citrullinated protein antibody-mediated inflammation in rheumatoid arthritis. Arthritis Rheumatol. 2014;66:813–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Takeuchi T, Miyasaka N, Inui T, et al. High titers of both rheumatoid factor and anti-CCP antibodies at baseline in patients with rheumatoid arthritis are associated with increased circulating baseline TNF level, low drug levels, and reduced clinical responses: a post hoc analysis of the RI. Arthritis Res Ther. 2017;9(1):1–11.

    Google Scholar 

  15. Matsuno H, Yudoh K, Katayama R, et al. The role of TNF-alpha in the pathogenesis of inflammation and joint destruction in rheumatoid arthritis (RA): a study using a human RA/SCID mouse chimera. Rheumatology (Oxford). 2002;41:329–37.

    Article  CAS  Google Scholar 

  16. Croft M, Siegel RM. Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases. Nat Rev Rheumatol. 2017;13:217–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Petrovic-Rackov L, Pejnovic N. Clinical significance of IL-18, IL-15, IL-12 and TNF-measurement in rheumatoid arthritis. Clin Rheumatol. 2006;25:448–52.

    Article  PubMed  Google Scholar 

  18. Posch PE, Cruz I, Bradshaw D, Medhekar BA. Novel polymorphisms and the definition of promoter “alleles” of the tumor necrosis factor and lymphotoxin α loci: inclusion in HLA haplotypes. Genes Immun. 2003;4:547–58.

    Article  CAS  PubMed  Google Scholar 

  19. El-Tahan RR, Ghoneim AM, El-Mashad N. TNF-α gene polymorphisms and expression. Springerplus. 2016;5:1508.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Umare VD, Pradhan VD, Rajadhyaksha AG, Patwardhan MM, Ghosh K, Nadkarni AH. Impact of TNF-α and LTα gene polymorphisms on genetic susceptibility in Indian SLE patients. Hum Immunol. 2017;78:201–8.

    Article  CAS  PubMed  Google Scholar 

  21. Messer G, Spengler U, Jung MC, et al. Polymorphic structure of the tumor necrosis factor (TNF) locus: an NcoI polymorphism in the first intron of the human TNF-beta gene correlates with a variant amino acid in position 26 and a reduced level of TNF-beta production. J Exp Med. 1991;173:209–19.

    Article  CAS  PubMed  Google Scholar 

  22. Santos MJ, Fernandes D, Caetano-Lopes J, et al. Lymphotoxin-α 252 G%3eA polymorphism: a link between disease susceptibility and dyslipidemia in rheumatoid arthritis? J Rheumatol. 2011;38:1244–9.

    Article  CAS  PubMed  Google Scholar 

  23. Parks CG, Pandey JP, Dooley MA, et al. Genetic polymorphisms in tumor necrosis factor (TNF)-α and TNF-β in a population-based study of systemic lupus erythematosus: associations and interaction with the interleukin-1α-889 C/T polymorphism. Hum Immunol. 2004;65:622–31.

    Article  CAS  PubMed  Google Scholar 

  24. Kallaur AP, Oliveira SR, Simão ANC, et al. Tumor necrosis factor beta (TNF-β) NcoI polymorphism is associated with multiple sclerosis in Caucasian patients from Southern Brazil independently from HLA-DRB1. J Mol Neurosci. 2014;53:211–21.

    Article  CAS  PubMed  Google Scholar 

  25. Laddha NC, Dwivedi M, Gani AR, Mansuri MS, Begum R. Tumor necrosis factor B (TNFB) genetic variants and its increased expression are associated with vitiligo susceptibility. PLoS ONE. 2013;8:e81736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pandey JP, Takeuchi F. TNF-α and TNF-β gene polymorphisms in systemic sclerosis. Hum Immunol. 1999;60:1128–30.

    Article  CAS  PubMed  Google Scholar 

  27. Bolstad AI, Le Hellard S, Kristjansdottir G, et al. Association between genetic variants in the tumour necrosis factor/lymphotoxin α/lymphotoxin β locus and primary Sjögren’s syndrome in Scandinavian samples. Ann Rheum Dis. 2012;71:981–8.

    Article  CAS  PubMed  Google Scholar 

  28. Al-Rayes H, Al-Swailem R, Albelawi M, Arfin M, Al-Asmari A, Tariq M. TNF-α and TNF-β gene polymorphism in Saudi rheumatoid arthritis patients. Clin Med Insights Arthritis Musculoskelet Disord. 2011;4:55–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Panoulas VF, Nikas SN, Smith JP, et al. Lymphotoxin 252A%3eG polymorphism is common and associates with myocardial infarction in patients with rheumatoid arthritis. Ann Rheum Dis. 2008;67:1550–6.

    Article  CAS  PubMed  Google Scholar 

  30. Karray EF, Bendhifallah I, Benabdelghani K, Hamzaoui K, Zakraoui L. Tumor necrosis factor gene polymorphisms and susceptibility to rheumatoid arthritis in regional Tunisian population. J Infect Dis Immun. 2011;3:30–5.

    Google Scholar 

  31. Saad MN, Mabrouk MS, Eldeib AM, Shaker OG. Genetic case-control study for eight polymorphisms associated with rheumatoid arthritis. PLoS ONE. 2015;10:1–15.

    Article  CAS  Google Scholar 

  32. Vinasco J, Beraún Y, Nieto A, et al. Polymorphism at the TNF loci in rheumatoid arthritis. Tissue Antigens. 1997;49:74–8.

    Article  CAS  PubMed  Google Scholar 

  33. Vandevyver C, Raus P, Stinissen P, Philippaerts L, Cassiman JJ, Raus J. Polymorphism of the tumour necrosis factor beta gene in multiple sclerosis and rheumatoid arthritis. Eur J Immunogenet. 1994;21:377–82.

    Article  CAS  PubMed  Google Scholar 

  34. Takeuchi F, Nabeta H, Hong GH, et al. The genetic contribution of the TNFa11 microsatellite allele and the TNFb + 252*2 allele in Japanese RA. Clin Exp Rheumatol. 2005;23:494–8.

    CAS  PubMed  Google Scholar 

  35. Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010;69:1580–8.

    Article  PubMed  Google Scholar 

  36. Prevoo MLL, Van’T Hof MA, Kuper HH, Van Leeuwen MA, Van De Putte LBA, Van Riel PLCM. Modified disease activity scores that include twenty-eight-joint counts development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995;38:44–8.

    Article  CAS  PubMed  Google Scholar 

  37. IBGE. Characteristics of the population and households: results of the universe. Charact. Popul. Households Results Universe. 2011. https://www.ibge.gov.br/english/estatistica/populacao/censo2010/caracteristicas%7B_%7Dda%7B_%7Dpopulacao/default%7B_%7Dcaracteristicas%7B_%7Dda%7B_%7Dpopulacao.shtm. Accessed 8 Feb 2015.

  38. Delongui F, Grion CMC, Watanabe MAE, et al. Association of tumor necrosis factor β genetic polymorphism and sepsis susceptibility. Exp Ther Med. 2011;2:349–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhang C, Zhao MQ, Liu J, et al. Association of lymphotoxin alpha polymorphism with systemic lupus erythematosus and rheumatoid arthritis: a meta-analysis. Int J Rheum Dis. 2015;18:398–407.

    Article  CAS  PubMed  Google Scholar 

  40. Rantapää-Dahlqvist S, De Jong BAW, Berglin E, et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 2003;48:2741–9.

    Article  CAS  PubMed  Google Scholar 

  41. Chang K, Yang SM, Kim SH, Han KH, Park SJ, Shin JII. Smoking and rheumatoid arthritis. Int J Mol Sci. 2014;15:22279–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Redlich K, Smolen JS. Inflammatory bone loss: pathogenesis and therapeutic intervention. Nat Rev Drug Discov. 2012;11:234–50.

    Article  CAS  PubMed  Google Scholar 

  43. Shaker OG, Alnoury AM, Hegazy GA, El Haddad HE, Sayed S, Hamdy A. Redutase, fator de crescimento transformador Β1 E linfotoxina-Α E susceptibilidade À artrite reumatoide. Rev Bras Reumatol. 2016;56:414–20.

    Article  Google Scholar 

  44. Vázquez-Del Mercado M, Nuñez-Atahualpa L, Figueroa-Sánchez M, et al. Serum levels of anticyclic citrullinated peptide antibodies, interleukin-6, tumor necrosis factor-α, and C-reactive protein are associated with increased carotid intima-media thickness: a cross-sectional analysis of a cohort of rheumatoid arthritis patients without cardiovascular risk factors. Biomed Res Int. 2015;2015:1–10.

    Google Scholar 

  45. Hecht C, Englbrecht M, Rech J, et al. Additive effect of anti-citrullinated protein antibodies and rheumatoid factor on bone erosions in patients with RA. Ann Rheum Dis. 2015;74:2151–6.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The study was supported by grants from the Coordination for the Improvement of Higher Level of Education Personnel (CAPES) of Brazilian Ministry of Education; Institutional Program for Scientific Initiation Scholarship (PIBIC) of the National Council for Scientific and Technological Development (CNPq); and State University of Londrina (PROPPG). We thank the University Hospital of State University of Londrina for technical supports.

Author information

Authors and Affiliations

Authors

Contributions

FAM, DFA, MABL, ERDA, TF, and NLM performed the laboratory analysis; TMVI and NTC: enhanced patient care; DFA and ANCS: performed the statistical analysis; FAM, DFA, ER, MABL, ERDA and ANCS: did the study design, discussed and interpreted the results obtained the results; ID and ANCS: they wrote the manuscript.

Corresponding author

Correspondence to Andréa Name Colado Simão.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

All the participants included in this study provided written informed consent.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

de Medeiros, F.A., Alfieri, D.F., Iriyoda, T.M.V. et al. TNF-β +252 A>G (rs909253) polymorphism is independently associated with presence of autoantibodies in rheumatoid arthritis patients . Clin Exp Med 19, 347–356 (2019). https://doi.org/10.1007/s10238-019-00556-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10238-019-00556-9

Keywords

Navigation