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


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.


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



Analysis of variance


Anticyclic citrullinated peptide antibodies


C-reactive protein


Ethylenediaminetetraacetic acid


Erythrocyte sedimentation rate


High-sensitivity C-reactive protein


Human leukocyte antigen




Natural logarithmic


Lymphotoxin A




Polymerase chain reaction


Rheumatoid arthritis


Rheumatoid factor


Standard of main


Soluble TNF receptor 1


Soluble TNF receptor 2


Tumor necrosis factor receptor 1


Tumor necrosis factor receptor 2


Tumor necrosis factor-alpha


Tumor necrosis factor-β



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.


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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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