Skip to main content

Advertisement

SpringerLink
Log in

TGFB1 (rs1800470 and rs1800469) variants are independently associated with disease activity and autoantibodies in rheumatoid arthritis patients

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

Abstract

To evaluate the association between TGFB1 + 869 T > C (rs1800470) and TGFB1-509 C > T (rs1800469) variants with susceptibility for rheumatoid arthritis (RA), disease activity, presence of rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) and TGF-β1 plasma levels. A total of 262 patients with RA and 168 control individuals were tested for the TGFB1 variants using a TaqMan genotyping assay. Disease activity score in 28 joints (DAS28) classified RA patients into two groups of disease activity: remission/mild (DAS28 < 3.2) and moderate/severe (DAS28 ≥ 3.2). TGFB1 + 869 T > C and −509 C > T variants, independently or in haplotype combination, were not associated with RA’s susceptibility. Patients with the TGFB1-509 TT genotype had a higher frequency of DAS28 ≥ 3.2 (OR 2.58, 95% CI 1.04–6.42, p = 0.041). The TGFB1 + 869 CC genotype in seropositive patients for RF or anti-CCP was associated with decreased TGF-β1 levels (p = 0.032 and p = 0.039, respectively). Patients with the TGFB1 + 869 C allele and elevated RF titles demonstrated a higher frequency of DAS28 ≥ 3.2 (p = 0.037). The TGFB1 + 869 T > C variant was associated with diminished TGF-β1 plasma levels and moderate/severe activity disease only in seropositive RF patients. This is the first study showing that TGF-β1 plasma levels can be modulated by the interaction between the TGFB1 + 869 T > C variant and autoantibodies. However, the TGFB1-509 C > T variant was associated with moderate/severe activity disease, independently of autoantibodies positivity. Thus, our findings suggest that TGFB1 + 869 T > C and −509 C > T variants can predict activity disease in different RA patient subgroups.

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

Access this article

Log in via an institution

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

References

  1. Mateen S, Zafar A, Moin S, Khan AQ, Zubair S. Understanding the role of cytokines in the pathogenesis of rheumatoid arthritis. Clin Chim Acta. 2016;455:161–71.

    Article  CAS  PubMed  Google Scholar 

  2. Guo Q, Wang Y, Xu D, Nossent J, Pavlos NJ, Xu J. Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res. 2018;6(1):15.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Malmström V, Catrina AI, Klareskog L. The immunopathogenesis of seropositive rheumatoid arthritis: from triggering to targeting. Nat Rev Immunol. 2017;17(1):60–75.

    Article  PubMed  Google Scholar 

  4. Ingegnoli F, Castelli R, Gualtierotti R. Rheumatoid factors: clinical applications. Dis Markers. 2013;35(6):727–34.

    Article  PubMed  PubMed Central  Google Scholar 

  5. 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(10):2741–9.

    Article  PubMed  Google Scholar 

  6. Sokolove J, Zhao X, Chandra PE, Robinson WH. Immune complexes containing citrullinated fibrinogen costimulate macrophages via Toll-like receptor 4 and Fcγ receptor. Arthritis Rheum. 2011;63(1):53–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Niu Q, Cai B, Huang Z, Shi Y, Wang L. Disturbed Th17/Treg balance in patients with rheumatoid arthritis. Rheumatol Int. 2012;32(9):2731–6.

    Article  CAS  PubMed  Google Scholar 

  8. Wang X, Yang C, Xu F, Qi L, Wang J, Yang P. Imbalance of circulating Tfr/Tfh ratio in patients with rheumatoid arthritis. Clin Exp Med. 2019;19(1):55–64.

    Article  CAS  PubMed  Google Scholar 

  9. Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol. 2005;6(4):345–52.

    Article  CAS  PubMed  Google Scholar 

  10. Zheng SG, Wang J, Wang P, Gray JD, Horwitz DA. IL-2 Is essential for TGF-β to convert naive CD4 + CD25 − Cells to CD25 + Foxp3 + regulatory T CELLS AND FOR EXPANSION OF THESE CELLS. J Immunol. 2007;178(4):2018–27.

    Article  CAS  PubMed  Google Scholar 

  11. Li MO, Wan YY, Sanjabi S, Robertson A-KL, Flavell RA. Transforming growth factor-β regulation of immune responses. Annu Rev Immunol. 2006;24(1):99–146.

    Article  CAS  PubMed  Google Scholar 

  12. Paradowska-Gorycka A, Trefler J, Maciejewska-Stelmach J, Łącki JK. Interleukin-10 gene promoter polymorphism in Polish rheumatoid arthritis patients. Int J Immunogenet. 2010;37(4):225–31.

    Article  CAS  PubMed  Google Scholar 

  13. de Medeiros FA, Alfieri DF, Iriyoda TMV, et al. TNF-β +252 A>G (rs909253) polymorphism is independently associated with presence of autoantibodies in rheumatoid arthritis patients. Clin Exp Med. 2019;19(3):347–56.

    Article  PubMed  Google Scholar 

  14. Zhou T-B, Zhao H-L, Fang S-L, Drummen GPC. Association of transforming growth factor-β1 T869C, G915C, and C509T gene polymorphisms with rheumatoid arthritis risk. J Recept Signal Transduct. 2014;34(6):469–75.

    Article  Google Scholar 

  15. Lee YH, Bae S-C. Association between circulating transforming growth factor-β1 level and polymorphisms in systemic lupus erythematosus and rheumatoid arthritis: a meta-analysis. Cell Mol Biol (Noisy-le-grand). 2017;63(1):53–9.

    Article  CAS  Google Scholar 

  16. Yamada Y, Okuizumi H, Miyauchi A, Takagi Y, Ikeda K, Harada A. Association of transforming growth factor β1 genotype with spinal osteophytosis in Japanese women. Arthritis Rheum. 2000;43(2):452.

    Article  CAS  PubMed  Google Scholar 

  17. Hussein YM, Mohamed RH, El-Shahawy EE, Alzahrani SS. Interaction between TGF-β1 (869C/T) polymorphism and biochemical risk factor for prediction of disease progression in rheumatoid arthritis. Gene. 2014;536(2):393–7.

    Article  CAS  PubMed  Google Scholar 

  18. Shah R, Rahaman B, Hurley CK, Posch PE. Allelic diversity in the TGFB1 regulatory region: characterization of novel functional single nucleotide polymorphisms. Hum Genet. 2006;119(1–2):61–74.

    Article  CAS  PubMed  Google Scholar 

  19. Cao H, Zhou Q, Lan R, et al. A Functional Polymorphism C-509T in TGFβ-1 Promoter Contributes to Susceptibility and Prognosis of Lone Atrial Fibrillation in Chinese Population. Jeyaseelan K, ed. PLoS One. 2014; 9(11):e112912.

  20. Guo W, Dong Z, Guo Y, et al. Polymorphisms of transforming growth factor-β1 associated with increased risk of gastric cardia adenocarcinoma in north China. Int J Immunogenet. 2011;38(3):215–24.

    Article  CAS  PubMed  Google Scholar 

  21. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of rheumatology/European league against rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569–81.

    Article  PubMed  Google Scholar 

  22. Anderson J, Caplan L, Yazdany J, et al. Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice. Arthritis Care Res (Hoboken). 2012;64(5):640–7.

    Article  Google Scholar 

  23. Sole X, Guino E, Valls J, Iniesta R, Moreno V. SNPStats: a web tool for the analysis of association studies. Bioinformatics. 2006;22(15):1928–9.

    Article  CAS  PubMed  Google Scholar 

  24. de Paz B, Alperi-López M, Ballina-García FJ, Prado C, Gutiérrez C, Suárez A. Cytokines and regulatory T cells in rheumatoid arthritis and their relationship with response to corticosteroids. J Rheumatol. 2010;37(12):2502–10.

    Article  PubMed  Google Scholar 

  25. Hashemi V, Farrokhi AS, Tanomand A, et al. Polymorphism of Foxp3 gene affects the frequency of regulatory T cells and disease activity in patients with rheumatoid arthritis in Iranian population. Immunol Lett. 2018;204:16–22.

    Article  CAS  PubMed  Google Scholar 

  26. Sanjabi S, Oh SA, Li MO. Regulation of the immune response by TGF-β: from conception to autoimmunity and infection. Cold Spring Harb Perspect Biol. 2017;9(6):a022236.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Chen D-Y, Chen Y-M, Chen H-H, Hsieh C-W, Lin C, Lan J-L. The associations of circulating CD4 + CD25 high regulatory T cells and TGF-β with disease activity and clinical course in patients with adult-onset Still’s disease. Connect Tissue Res. 2010;51(5):370–7.

    Article  CAS  PubMed  Google Scholar 

  28. Jin T, Almehed K, Carlsten H, Forsblad-d’Elia H. Decreased serum levels of TGF-β1 are associated with renal damage in female patients with systemic lupus erythematosus. Lupus. 2012;21(3):310–8.

    Article  CAS  PubMed  Google Scholar 

  29. Zhang L, Yan J, Wang Y-X, et al. Association of TGF-β1 +869C/T promoter polymorphism with susceptibility to autoimmune diseases: a meta-analysis. Mol Biol Rep. 2013;40(8):4811–7.

    Article  CAS  PubMed  Google Scholar 

  30. Kobayashi T, Murasawa A, Ito S, et al. Cytokine gene polymorphisms associated with rheumatoid arthritis and periodontitis in Japanese adults. J Periodontol. 2009;80(5):792–9.

    Article  CAS  PubMed  Google Scholar 

  31. Alayli G, Kara N, Tander B, Canturk F, Gunes S, Bagci H. Association of transforming growth factor β1 gene polymorphism with rheumatoid arthritis in a Turkish population. Jt Bone Spine. 2009;76(1):20–3.

    Article  CAS  Google Scholar 

  32. Panoulas VF, Douglas KMJ, Smith JP, et al. Transforming growth factor- 1 869T/C, but not interleukin-6 -174G/C, polymorphism associates with hypertension in rheumatoid arthritis. Rheumatology. 2008;48(2):113–8.

    Article  PubMed  Google Scholar 

  33. Pokorny V. Transforming growth factor 1 gene (HSTGFB1) nucleotide T869C (codon 10) polymorphism is not associated with prevalence or severity of rheumatoid arthritis in a Caucasian population. Ann Rheum Dis. 2003;62(9):907–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kim S, Han S, Kim G, Lee J, Kang Y. TGF-ß1 polymorphism determines the progression of joint damage in rheumatoid arthritis. Scand J Rheumatol. 2004;33(6):389–94.

    Article  CAS  PubMed  Google Scholar 

  35. Patel SL, Prakash J, Gupta V. TGF-β1 +869C/T polymorphism increases susceptibility to rheumatoid arthritis in North Indian population. Clin Rheumatol. 2020;39(10):2881–8.

    Article  PubMed  Google Scholar 

  36. Sugiura Y. Transforming growth factor beta1 gene polymorphism in rheumatoid arthritis. Ann Rheum Dis. 2002;61(9):826–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Saad MN, Mabrouk MS, Eldeib AM, Shaker OG. Genetic Case-Control Study for Eight Polymorphisms Associated with Rheumatoid Arthritis. Garcia de Frutos P, ed. PLoS One. 2015; 10(7):e0131960.

  38. Sun W, Yi M, Bai Y, et al. Correlations between the polymorphism of +869T/C in TGF-β1 and rheumatoid arthritis. J Musculoskelet Neuronal Interact. 2019;19(1):127–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Yamamoto K, Okada Y, Suzuki A, Kochi Y. Genetics of rheumatoid arthritis in Asia–present and future. Nat Rev Rheumatol. 2015;11(6):375–9.

    Article  CAS  PubMed  Google Scholar 

  40. Ceccarelli F, Perricone C, Fabris M, et al. Transforming growth factor β 869C/T and interleukin 6–174G/C polymorphisms relate to the severity and progression of bone-erosive damage detected by ultrasound in rheumatoid arthritis. Arthritis Res Ther. 2011;13(4):R111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Coutant F. Pathogenic effects of anti-citrullinated protein antibodies in rheumatoid arthritis – role for glycosylation. Jt Bone Spine. 2019;86(5):562–7.

    Article  CAS  Google Scholar 

  42. Scherer HU, van der Woude D, Ioan-Facsinay A, et al. Glycan profiling of anti-citrullinated protein antibodies isolated from human serum and synovial fluid. Arthritis Rheum. 2010;62(6):1620–9.

    Article  CAS  PubMed  Google Scholar 

  43. Reparon-Schuijt CC, van Esch WJE, van Kooten C, et al. Secretion of anti-citrulline-containing peptide antibody by B lymphocytes in rheumatoid arthritis. Arthritis Rheum. 2001;44(1):41–7.

    Article  CAS  PubMed  Google Scholar 

  44. Innala L, Kokkonen H, Eriksson C, Jidell E, Berglin E, Dahlqvst SR. Antibodies against mutated citrullinated vimentin are a better predictor of disease activity at 24 months in early rheumatoid arthritis than antibodies against cyclic citrullinated peptides. J Rheumatol. 2008;35(6):1002–8.

    PubMed  Google Scholar 

  45. Chen Y, Dawes PT, Packham JC, Mattey DL. Interaction between smoking and functional polymorphism in the TGFB1 gene is associated with ischaemic heart disease and myocardial infarction in patients with rheumatoid arthritis: a cross-sectional study. Arthritis Res Ther. 2012;14(2):R81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Welsing PMJ, Landewé RBM, Van Riel PLCM, et al. The relationship between disease activity and radiologic progression in patients with rheumatoid arthritis: a longitudinal analysis. Arthritis Rheum. 2004;50(7):2082–93.

    Article  PubMed  Google Scholar 

  47. Kavanaugh A, Fleischmann RM, Emery P, et al. Clinical, functional and radiographic consequences of achieving stable low disease activity and remission with adalimumab plus methotrexate or methotrexate alone in early rheumatoid arthritis: 26-week results from the randomised, controlled OPTIMA study. Ann Rheum Dis. 2013;72(1):64–71.

    Article  CAS  PubMed  Google Scholar 

  48. Smolen JS, Van Der Heijde DMFM, St.Clair EW, , et al. Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: results from the ASPIRE trial. Arthritis Rheum. 2006;54(3):702–10.

    Article  CAS  PubMed  Google Scholar 

  49. Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73(3):492–509.

    Article  CAS  PubMed  Google Scholar 

  50. Smolen JS, Breedveld FC, Burmester GR, et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis. 2016;75(1):3–15.

    Article  PubMed  Google Scholar 

  51. Terry CF, Loukaci V, Green FR. Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem. 2000;275(24):18138–44.

    Article  CAS  PubMed  Google Scholar 

  52. Martelossi Cebinelli GC, Paiva Trugilo K, Badaró Garcia S, Brajão de Oliveira K. TGF-β1 functional polymorphisms: a review. Eur Cytokine Netw. 2016;27(4):81–9.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the University Hospital of State University of Londrina for technical and administrative supports. This research received no specific grant from any funding agency.

Funding

This research received no specific grant from any funding agency.

Author information

Authors and Affiliations

  1. Department of Rheumatology, Pontifical Catholic University of Paraná, Londrina, PR, Brazil

    Tatiana Mayumi Veiga Iriyoda

  2. Laboratory of Research in Applied Immunology, Health Sciences Center, State University of Londrina, Londrina, PR, Brazil

    Tatiana Mayumi Veiga Iriyoda, Tamires Flauzino, Marcell Alysson Batisti Lozovoy, Edna Maria Vissoci Reiche & Andréa Name Colado Simão

  3. Department of Rheumatology, State University of Londrina, Londrina, PR, Brazil

    Neide Tomimura Costa

  4. Department of Pathology, Clinical Analysis and Toxicology, Health Sciences Center, University Hospital, State University of Londrina, Av. RobertKoch 60, Londrina, PR, Brazil

    Marcell Alysson Batisti Lozovoy, Edna Maria Vissoci Reiche & Andréa Name Colado Simão

Authors
  1. Tatiana Mayumi Veiga Iriyoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tamires Flauzino
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Neide Tomimura Costa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marcell Alysson Batisti Lozovoy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Edna Maria Vissoci Reiche
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andréa Name Colado Simão
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception and research design: Andréa Name Colado Simão, Tamires Flauzino; Manuscript writing and discussion of results: Andréa Name Colado Simão, Tamires Flauzino, Edna Maria Vissoci Reiche, Tatiana Mayumi Veiga Iriyoda; Data collection: Tamires Flauzino, Tatiana Mayumi Veiga Iriyoda, Neide Tomimura Costa; Laboratory analysis: Tamires Flauzino, Marcell Alysson Batisti Lozovoy; Statistical analysis: Andréa Name Colado Simão, Tamires Flauzino. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Andréa Name Colado Simão.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Ethical approval

This study was conducted after approval by the Institutional Research Ethics Committees of University of Londrina, Paraná, Brazil (CAAE: 06405812.1.0000.5231). 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.

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

Iriyoda, T.M.V., Flauzino, T., Costa, N.T. et al. TGFB1 (rs1800470 and rs1800469) variants are independently associated with disease activity and autoantibodies in rheumatoid arthritis patients. Clin Exp Med 22, 37–45 (2022). https://doi.org/10.1007/s10238-021-00725-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10238-021-00725-9

Keywords

Search

Navigation