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Clinical and Experimental Medicine

, Volume 19, Issue 3, pp 347–356 | Cite as

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

  • Fabiano Aparecido de Medeiros
  • Daniela Frizon Alfieri
  • Tatiana Mayumi Veiga Iriyoda
  • Neide Tomimura Costa
  • Elaine Regina Delicato de Almeida
  • Marcell Alysson Batisti Lozovoy
  • Naiara Lourenço Mari
  • Tamires Flauzino
  • Edna Maria Vissoci Reiche
  • Isaias Dichi
  • Andréa Name Colado SimãoEmail author
Original Article
  • 32 Downloads

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.

Keywords

Rheumatoid Arthritis TNF-β +252 A>G polymorphism rs909253 Rheumatoid factor Tumor necrosis factor alpha Anticyclic citrullinated peptide antibodies 

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

Notes

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’s contribution

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.

Compliance with ethical standards

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.

References

  1. 1.
    Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet. 2010;376:1094–108.CrossRefGoogle Scholar
  2. 2.
    Isaacs JD. The changing face of rheumatoid arthritis: sustained remission for all? Nat Rev Immunol. 2010;10:605–11.CrossRefGoogle Scholar
  3. 3.
    Li S, Yu Y, Yue Y, Zhang Z, Su K. Microbial infection and rheumatoid arthritis. J Clin Cell Immunol. 2013;4:174.Google Scholar
  4. 4.
    Weyand CM, Goronzy JJ. Association of MHC and rheumatoid arthritis: HLA polymorphisms in phenotypic variants of rheumatoid arthritis. Arthritis Res. 2000;2:212.CrossRefGoogle Scholar
  5. 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.CrossRefGoogle Scholar
  6. 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.Google Scholar
  7. 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.CrossRefGoogle Scholar
  8. 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.CrossRefGoogle Scholar
  9. 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.CrossRefGoogle Scholar
  10. 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.CrossRefGoogle Scholar
  11. 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.CrossRefGoogle Scholar
  12. 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.CrossRefGoogle Scholar
  13. 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.CrossRefGoogle Scholar
  14. 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. 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.CrossRefGoogle Scholar
  16. 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.CrossRefGoogle Scholar
  17. 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.CrossRefGoogle Scholar
  18. 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.CrossRefGoogle Scholar
  19. 19.
    El-Tahan RR, Ghoneim AM, El-Mashad N. TNF-α gene polymorphisms and expression. Springerplus. 2016;5:1508.CrossRefGoogle Scholar
  20. 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.CrossRefGoogle Scholar
  21. 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.CrossRefGoogle Scholar
  22. 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.CrossRefGoogle Scholar
  23. 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.CrossRefGoogle Scholar
  24. 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.CrossRefGoogle Scholar
  25. 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.CrossRefGoogle Scholar
  26. 26.
    Pandey JP, Takeuchi F. TNF-α and TNF-β gene polymorphisms in systemic sclerosis. Hum Immunol. 1999;60:1128–30.CrossRefGoogle Scholar
  27. 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.CrossRefGoogle Scholar
  28. 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.CrossRefGoogle Scholar
  29. 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.CrossRefGoogle Scholar
  30. 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. 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.CrossRefGoogle Scholar
  32. 32.
    Vinasco J, Beraún Y, Nieto A, et al. Polymorphism at the TNF loci in rheumatoid arthritis. Tissue Antigens. 1997;49:74–8.CrossRefGoogle Scholar
  33. 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.CrossRefGoogle Scholar
  34. 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.Google Scholar
  35. 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.CrossRefGoogle Scholar
  36. 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.CrossRefGoogle Scholar
  37. 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. 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.CrossRefGoogle Scholar
  39. 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.CrossRefGoogle Scholar
  40. 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.CrossRefGoogle Scholar
  41. 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.CrossRefGoogle Scholar
  42. 42.
    Redlich K, Smolen JS. Inflammatory bone loss: pathogenesis and therapeutic intervention. Nat Rev Drug Discov. 2012;11:234–50.CrossRefGoogle Scholar
  43. 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.CrossRefGoogle Scholar
  44. 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. 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.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Fabiano Aparecido de Medeiros
    • 1
  • Daniela Frizon Alfieri
    • 1
  • Tatiana Mayumi Veiga Iriyoda
    • 2
  • Neide Tomimura Costa
    • 3
  • Elaine Regina Delicato de Almeida
    • 4
  • Marcell Alysson Batisti Lozovoy
    • 4
  • Naiara Lourenço Mari
    • 1
  • Tamires Flauzino
    • 1
  • Edna Maria Vissoci Reiche
    • 4
  • Isaias Dichi
    • 3
  • Andréa Name Colado Simão
    • 4
    Email author
  1. 1.Research Laboratory in Applied ImmunologyUniversity of LondrinaLondrinaBrazil
  2. 2.Department of RheumatologyPUC, Pontifícia Universidade CatólicaLondrinaBrazil
  3. 3.Department of Internal MedicineUniversity of LondrinaLondrinaBrazil
  4. 4.Department of Pathology, Clinical Analysis and ToxicologyUniversity of LondrinaLondrinaBrazil

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