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Polymorphism in the tumor necrosis factor-α gene promoter is associated with severity of rheumatoid arthritis in the Czech population

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Abstract

Rheumatoid arthritis (RA) is a model of multigenic inflammatory disorder in which tumor necrosis factor-α (TNF-α) plays an important role. Genetic factors may be implicated in the susceptibility to disease initiation as well as in severity of disease course. Elevated levels of TNF-α in the plasma and synovial fluid from RA patients may be associated with polymorphisms in the promoter region of the TNF-α gene. The aim of this study was to elucidate putative association between the −308 G/A polymorphism in the promoter region of the TNF-α gene and susceptibility to onset and severity of RA. A total of 130 RA patients and a control group of 150 healthy subjects with similar age and sex distribution were available for the study. All patients fulfilled the American College of Rheumatology revised criteria for RA. RA patients had a disease duration of at least 2 years. Radiographs of both hands of all RA patients were scored with the Steinbrocker method. There were 15 patients of stage I (nonerosive form) of RA and 114 patients of stages II–IV (erosive form). To assess the RA patient’s functional ability, the Health Assessment Questionnaire (HAQ) was used. The −308 G/A promoter polymorphism of the TNF-α gene was detected by polymerase chain reaction and restriction fragment length polymorphism analysis. No differences in genotype distribution and allelic frequences of −308 G/A TNF-α promoter polymorphism have been found between RA patients and the control group. Significant differences have been observed within the RA group divided according to the radiographic progression of disease based on the Steinbrocker radiographic score and functional ability (HAQ). These results suggest an association of the −308 G/A polymorphism of the TNF-α gene with the severity of RA.

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References

  1. Reveille JD (1998) The genetic contribution to the pathogenesis of rheumatoid arthritis. Curr Opin Rheumatol 10:187–200

    Article  PubMed  CAS  Google Scholar 

  2. Goldring SR (2003) Pathogenesis of bone and cartilage destruction in rheumatoid arthritis. Rheumatology (Oxford) 42(Suppl 2):ii11–ii16

    CAS  Google Scholar 

  3. Harney SM, Newton JL, Wordsworth BP (2003) Molecular genetics of rheumatoid arthritis. Curr Opin Pharmacol 3:280–285

    Article  PubMed  CAS  Google Scholar 

  4. Lawrence RC, Helmick GG, Arnett FC et al (1998) Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 41:778–799

    Article  PubMed  CAS  Google Scholar 

  5. MacGregor AJ, Snieder H, Rigby AS et al (2000) Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum 43:30–37

    Article  PubMed  CAS  Google Scholar 

  6. Aho K, Koskenvuo M, Tuominen J, Kaprio J (1986) Occurrence of rheumatoid arthritis in a nationwide series of twins. J Rheumatol 13:899–902

    PubMed  CAS  Google Scholar 

  7. Winchester R (1994) The molecular basis of susceptibility to rheumatoid arthritis. Adv Immunol 56:389–466

    PubMed  CAS  Google Scholar 

  8. Ota M, Katsuyama Y, Kimura A et al (2001) A second susceptibility gene for developing rheumatoid arthritis in the human MHC is localized within a 70-kb interval telomeric of the TNF genes in the HLA class III region. Genomics 71:263–270

    Article  PubMed  CAS  Google Scholar 

  9. Zanelli E, Jones G, Pascual M et al (2001) The telomeric part of the HLA region predisposes to rheumatoid arthritis independently of the class II loci. Hum Immunol 62:75–84

    Article  PubMed  CAS  Google Scholar 

  10. Jawaheer D, Li W, Graham RR et al (2002) Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis. Am J Hum Genet 71:585–594

    Article  PubMed  CAS  Google Scholar 

  11. Ruuls SR, Sedgwick JD (1999) Unlinking tumor necrosis factor biology from the major histocompatibility complex: lessons from human genetics and animal models. Am J Hum Genet 65:294–301

    Article  PubMed  CAS  Google Scholar 

  12. Vassalli P (1992) The pathophysiology of tumor necrosis factors. Annu Rev Immunol 10:411–452

    Article  PubMed  CAS  Google Scholar 

  13. Hajeer AH, Hutchinson IV (2001) Influence of TNFalpha gene polymorphisms on TNFalpha production and disease. Hum Immunol 62:1191–1199

    Article  PubMed  CAS  Google Scholar 

  14. Waldron-Lynch F, Adams C, Shanahan F et al (1999) Genetics analysis of the 3′ untranslated region of the tumor necrosis factor shows a highly conserved region in rheumatoid arthritis affected and unaffected subjects. J Med Genet 36:214–216

    PubMed  CAS  Google Scholar 

  15. Cvetkovic JT, Wallberg-Jonsson S, Stegmayr B et al (2002) Susceptibility for and clinical manifestations of rheumatoid arthritis are associated with polymorphisms of the TNF-alpha, IL-1b, and IL-1Ra genes. J Rheumatol 29:212–219

    PubMed  CAS  Google Scholar 

  16. Wilson AG, de Vries N, van de Putte LB, Duff GW (1995) A tumour necrosis factor alpha polymorphism is not associated with rheumatoid arthritis. Ann Rheum Dis 54:601–603

    PubMed  CAS  Google Scholar 

  17. Brinkman BM, Huizinga TW, Kurban SS et al (1997) Tumour necrosis factor alpha gene polymorphisms in rheumatoid arthritis: association with susceptibility, or severity of disease? Br J Rheumatol 36:516–521

    Article  PubMed  CAS  Google Scholar 

  18. Rodriguez-Carreon AA, Zuniga J, Hernandez-Pacheco G et al (2005) Tumor necrosis factor-alpha −308 promoter polymorphism contributes independently to HLA alleles in the severity of rheumatoid arthritis in Mexicans. J Autoimmun 24:63–68

    Article  PubMed  CAS  Google Scholar 

  19. Danis VA, Millington M, Hyland V et al (1995) Increased frequency of the uncommon allele of a tumour necrosis factor alpha gene polymorphism in rheumatoid arthritis and systemic lupus erythematosus. Dis Markers 12:127–133

    PubMed  CAS  Google Scholar 

  20. Vinasco J, Beraun Y, Nieto A et al (1997) Polymorphism at the TNF loci in rheumatoid arthritis. Tissue Antigens 49:74–78

    PubMed  CAS  Google Scholar 

  21. Barton A, Platt H, Salway F et al (2004) Polymorphism in the tumour necrosis factor gene are not associated with severity of inflammatory polyarthritis. Ann Rheum Dis 63:280–284

    Article  PubMed  CAS  Google Scholar 

  22. Lacki JK, Moser R, Korczowska I et al (2000) TNF-alpha gene polymorphism does not affect the clinical and radiological outcome of rheumatoid arthritis. Rheumatol Int 19:137–140

    Article  PubMed  CAS  Google Scholar 

  23. Pawlik A, Florczak M, Ostanek L et al (2005) TNF-alpha −308 promoter polymorphism in patients with rheumatoid arthritis. Scand J Rheumatol 34:22–26

    Article  PubMed  CAS  Google Scholar 

  24. Arnett FC, Edworthy SM, Bloch DA et al (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324

    Article  PubMed  CAS  Google Scholar 

  25. Prevoo ML, van’t Hof MA, Kuper HH et al (1995) 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 38:44–48

    Article  PubMed  CAS  Google Scholar 

  26. Pincus T, Larsen A, Brooks RH et al (1997) Comparison of 3 quantitative measures of hand radiographs in patients with rheumatoid arthritis: Steinbrocker stage, Kaye modified Sharp score, and Larsen score. J Rheumatol 24:2106–2112

    PubMed  CAS  Google Scholar 

  27. Alsalameh S, Winter K, Al-Ward R et al (1999) Distribution of TNF-alpha, TNF-R55 and TNF-R75 in the rheumatoid synovial membrane: TNF receptors are localized preferentially on the lining layer; TNF-alpha is distributed mainly in the vicinity of the TNF-receptors in the deeper layers. Scand J Immunol 49:278–285

    Article  PubMed  CAS  Google Scholar 

  28. Marinova-Mutafchieva L, Williams RO, Mason LJ et al (1997) Dynamics of proinflammatory cytokine expression in the joints of mice with collagen-induced arthritis (CIA). Clin Exp Immunol 107:507–512

    Article  PubMed  CAS  Google Scholar 

  29. Weinblatt ME, Kremer JM, Bankhurst AD et al (1999) A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 340:253–259

    Article  PubMed  CAS  Google Scholar 

  30. Maini RN, Breedveld FC, Kalden JR et al (1998) Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 41:1552–1563

    Article  PubMed  CAS  Google Scholar 

  31. Maini R, St Clair EW, Breedveld F et al (1999) Infliximab (chimeric anti-tumour necrosis factor a monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 354:1932–1939

    Article  PubMed  CAS  Google Scholar 

  32. Lipsky PE, van der Heijde DM, St Clair EW et al (2000) Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med 343:1594–1602

    Article  PubMed  CAS  Google Scholar 

  33. Genovese MC, Bathon JM, Martin RW et al (2002) Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Arthritis Rheum 46:1443–1450

    Article  PubMed  CAS  Google Scholar 

  34. Weinblatt ME, Keystone EC, Furst DE et al (2003) Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 48:855

    Article  CAS  Google Scholar 

  35. Rau R (2002) Adalimumab (a fully human anti-tumour necrosis factor alpha monoclonal antibody) in the treatment of active rheumatoid arthritis: the initial results of five trials. Ann Rheum Dis 61(Suppl 2):ii70–ii73

    PubMed  CAS  Google Scholar 

  36. Seki N, Kamizono S, Yamada A et al (1999) Polymorphisms in the 5′-flanking region of tumor necrosis factor-alpha gene in patients with rheumatoid arthritis. Tissue Antigens 54:194–197

    Article  PubMed  CAS  Google Scholar 

  37. Braun N, Michel U, Ernst BP et al (1996) Gene polymorphism at position −308 of the tumor-necrosis-factor-alpha (TNF-alpha) in multiple sclerosis and it’s influence on the regulation of TNF-alpha production. Neurosci Lett 215:75–78

    PubMed  CAS  Google Scholar 

  38. Wilson AG, Symons JA, McDowell TL et al (1997) Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci USA 94:3195–3199

    Article  PubMed  CAS  Google Scholar 

  39. Kroeger KM, Carville KS, Abraham LJ (1997) The −308 tumor necrosis factor-alpha promoter polymorphism effects transcription. Mol Immunol 34:391–399

    Article  PubMed  CAS  Google Scholar 

  40. Brinkman BM, Huizinga TW, Breedveld FC, Verweij CL (1996) Allele-specific quantification of TNFA transcripts in rheumatoid arthritis. Hum Genet 97:813–818

    PubMed  CAS  Google Scholar 

  41. Stuber F, Petersen M, Bokelmann F, Schode U (1996) A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor-alpha concentrations and outcome of patients with severe sepsis. Crit Care Med 24:381–384

    Article  PubMed  CAS  Google Scholar 

  42. Pociot F, Briant L, Jongeneel CV et al (1993) Association of tumor necrosis factor (TNF) and class II major histocompatibility complex alleles with the secretion of TNF-alpha and TNF-beta by human mononuclear cells: a possible link to insulin-dependent diabetes mellitus. Eur J Immunol 23:224–231

    Article  PubMed  CAS  Google Scholar 

  43. Uglialoro AM, Turbay D, Pesavento PA et al (1998) Identification of three new single nucleotide polymorphisms in the human tumor necrosis factor-alpha gene promoter. Tissue Antigens 52:359–367

    Article  PubMed  CAS  Google Scholar 

  44. Brinkman BM, Zuijdeest D, Kaijzel EL et al (1995–1996) Relevance of the tumor necrosis factor α (TNF α) -308 promoter polymorphism in TNF α gene regulation. J Inflamm 46:32–41

    Google Scholar 

  45. Knight JC, Udalova I, Hill AV et al (1999) A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria. Nat Genet 22:145–150

    Article  PubMed  CAS  Google Scholar 

  46. Jacob CE, Fronek Z, Lewis GD et al (1990) Heritable major histocompatibility complex class II-associated differences in production of tumor necrosis factor alpha: relevance to genetic predisposition to systemic lupus erythematosus. Proc Natl Acad Sci USA 87:1233–1237

    Article  PubMed  CAS  Google Scholar 

  47. Legrand L, Lathrop GM, Bardin T et al (1987) HLA haplotypes in non-familial rheumatoid arthritis. Ann Rheum Dis 46:395–397

    Article  PubMed  CAS  Google Scholar 

  48. Newton JL, Harney SM, Timms AE et al (2004) Dissection of class III major histocompatibility complex haplotypes associated with rheumatoid arthritis. Arthritis Rheum 7:2122–2129

    Article  CAS  Google Scholar 

  49. Kochi Y, Yamada R, Kobayashi K et al (2004) Analysis of single-nucleotide polymorphisms in Japanese rheumatoid arthritis patients shows additional susceptibility markers beside the classic shared epitope susceptibility sequences. Arthritis Rheum 1:63–71

    Article  CAS  Google Scholar 

  50. Mugnier B, Balandraud N, Darque A et al (2003) Polymorphism at position −308 of the tumor necrosis factor alpha gene influences outcome of infliximab therapy in rheumatoid arthritis. Arthritis Rheum 48:1849–1852

    Article  PubMed  CAS  Google Scholar 

  51. Lee YH, Rho YH, Choi SJ et al (2006) Association of TNF-alpha −308 G/A polymorphism with responsiveness to TNF-alpha-blockers in rheumatoid arthritis: a metaanalysis. Rheumatol Int 27:157–161

    Article  PubMed  CAS  Google Scholar 

  52. Seitz M, Wirthmuller U, Moller B, Villiger PM (2007) The −308 tumour necrosis factor-{alpha} gene polymorphism predicts therapeutic response to TNF{alpha}-blockers in rheumatoid arthritis and spondyloarthritis patients. Rheumatology (Oxford) 46:93–96

    Article  CAS  Google Scholar 

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Acknowledgment

The study was supported by research project no. NR7812-3/2004, Ministry of Health of the Czech Republic.

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Authors and Affiliations

  1. Rheumatology Division, 2nd Department of Internal Medicine, St. Anne’s University Hospital, Pekařská 53, 656 91, Brno, Czech Republic

    Petr Nemec & Miroslav Soucek

  2. Institute of Pathological Physiology, Faculty of Medicine, Masaryk University, Komenského Náměstí 2, 662 43, Brno, Czech Republic

    Monika Pavkova-Goldbergova & Anna Vasku

  3. Institute of Clinical Immunology and Allergology, St. Anne’s University Hospital, Pekařská 53, 656 91, Brno, Czech Republic

    Martina Stouracova

  4. Institute of Rheumatology, Na Slupy 4, 128 50, Prague, Czech Republic

    Jindra Gatterova

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  1. Petr Nemec
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  2. Monika Pavkova-Goldbergova
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Correspondence to Petr Nemec.

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Nemec, P., Pavkova-Goldbergova, M., Stouracova, M. et al. Polymorphism in the tumor necrosis factor-α gene promoter is associated with severity of rheumatoid arthritis in the Czech population. Clin Rheumatol 27, 59–65 (2008). https://doi.org/10.1007/s10067-007-0653-7

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  • DOI: https://doi.org/10.1007/s10067-007-0653-7

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