Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Full Paper
  • Published:

Macrophage migration inhibitory factor (MIF) gene polymorphism is associated with susceptibility to but not severity of inflammatory polyarthritis

Genes & Immunity volume 4, pages 487–491 (2003)Cite this article

Abstract

The aim of the study was to investigate whether polymorphisms of macrophage migration inhibitory factor (MIF) determine susceptibility to or severity of inflammatory polyarthritis (IP). Genotypes for a single-nucleotide polymorphism (MIF-173*G/C) and a tetranucleotide (CATT)n repeat mapping to the promoter region of the MIF gene were compared between UK Caucasian IP cases (n=438) and controls (n=343). Both polymorphisms were also investigated for association with features of disease activity and severity at baseline and by 5 years. The MIF-173*C allele (OR 1.7, 95% CI 1.3–2.4, P=1.8 × 10−4) and the CATT7 allele (OR 1.5, 95% CI 1.0–2.1, P=0.02) were found to be associated with increased susceptibility to IP. Furthermore, presence of the haplotype containing both associated polymorphisms was associated with a three-fold increase risk of developing IP. No association with disease severity or activity either at baseline or by 5 years was detected for either of the promoter polymorphisms studied. In conclusion, MIF is a susceptibility gene for the development of IP. The same alleles previously reported to be associated with susceptibility to juvenile idiopathic arthritis account for the increased risk. The promoter polymorphisms of MIF, investigated in this study, do not influence the severity of disease outcome by 5 years.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

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

    Article  CAS  Google Scholar 

  2. Thomson W, Harrison B, Oilier B et al. Quantifying the exact role of HLA–DRB1 alleles in susceptibility to inflammatory polyarthritis: results from a large, population-based study. Arthritis Rheum 1999; 42: 757–762.

    Article  CAS  Google Scholar 

  3. Brennan P, Harrison B, Barrett E et al. A simple algorithm to predict the development of radiological erosions in patients with early rheumatoid arthritis: prospective cohort study. BMJ 1996; 313: 471–476.

    Article  CAS  Google Scholar 

  4. Lolis E . Glucocorticoid counter regulation: macrophage migration inhibitory factor as a target for drug discovery. Curr Opin Pharmacol 2001; 1: 662–668.

    Article  CAS  Google Scholar 

  5. Mikulowska A, Metz CN, Bucala R, Holmdahl R . Macrophage migration inhibitory factor is involved in the pathogenesis of collagen type II-induced arthritis in mice. J Immunol 1997; 158: 5514–5517.

    CAS  Google Scholar 

  6. Santos L, Hall P, Metz C, Bucala R, Morand EF . Role of macrophage migration inhibitory factor (MIF) in murine antigen-induced arthritis: interaction with glucocorticoids. Clin Exp Immunol 2001; 123: 309–314.

    Article  CAS  Google Scholar 

  7. Leech M, Metz C, Santos L et al. Involvement of macrophage migration inhibitory factor in the evolution of rat adjuvant arthritis. Arthritis Rheum 1998; 41: 910–917.

    Article  CAS  Google Scholar 

  8. Donn RP, Shelley E, Oilier WE, Thomson W . A novel 5′-flanking region polymorphism of macrophage migration inhibitory factor is associated with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum 2001; 44: 1782–1785.

    Article  CAS  Google Scholar 

  9. Donn R, Alourfi Z, De Benedetti F et al. Mutation screening of the macrophage migration inhibitory factor gene: positive association of a functional polymorphism of macrophage migration inhibitory factor with juvenile idiopathic arthritis. Arthritis Rheum 2002; 46: 2402–2409.

    Article  CAS  Google Scholar 

  10. Baugh JA, Chitnis S, Donnelly SC et al. A functional promoter polymorphism in the macrophage migration inhibitory factor (MIF) gene associated with disease severity in rheumatoid arthritis. Genes Immun 2002; 3: 170–176.

    Article  CAS  Google Scholar 

  11. Alourfi Z, Donn R, Ray D . Macrophage migration inhibitory factor (MIF) expression is differentially regulated by a functional interaction between two promoter polymorphisms. Rheumatology (Oxford), 2003; 42 (suppl): 6.

    Google Scholar 

  12. Onodera S, Nishihira J, Iwabuchi K et al. Macrophage migration inhibitory factor up-regulates matrix metalloproteinase-9 and -13 in rat osteoblasts. Relevance to intracellular signaling pathways. J Biol Chem 2002; 277: 7865–7874.

    Article  CAS  Google Scholar 

  13. Morand EF, Leech M, Weedon H, Metz C, Bucala R, Smith MD . Macrophage migration inhibitory factor in rheumatoid arthritis: clinical correlations. Rheumatology (Oxford) 2002; 41: 558–562.

    Article  CAS  Google Scholar 

  14. Donn RP, Zeggini E, Lamb et al. Linkage and association of macrophage migration inhibitory factor (MIF) with juvenile idiopathic arthritis. Rheumatology (Oxford), 2003; 42 (suppl.) 82.

    Google Scholar 

  15. Dugowson CE, Nelson JL, Koepsell TD . Evaluation of the 1987 revised criteria for rheumatoid arthritis in a cohort of newly diagnosed female patients. Arthritis Rheum. 1990; 33: 1042–1046.

    Article  CAS  Google Scholar 

  16. Leech M, Metz C, Bucala R, Morand EF . Regulation of macrophage migration inhibitory factor by endogenous glucocorticoids in rat adjuvant-induced arthritis. Arthritis Rheum 2000; 43: 827–833.

    Article  CAS  Google Scholar 

  17. de Jong YP, Abadia-Molina AC, Satoskar AR et al. Development of chronic colitis is dependent on the cytokine MIF. Nat Immunol 2001; 2: 1061–1066.

    Article  CAS  Google Scholar 

  18. Denkinger CM, Denkinger M, Kort JJ, Metz C, Forsthuber TG . In vivo blockade of macrophage migration inhibitory factor ameliorates acute experimental autoimmune encephalomyelitis by impairing the homing of encephalitogenic T cells to the central nervous system. J Immunol 2003; 170: 1274–1282.

    Article  CAS  Google Scholar 

  19. Symmons DP, Barrett EM, Bankhead CR, Scott DG, Silman AJ . The incidence of rheumatoid arthritis in the United Kingdom: results from the Norfolk Arthritis Register. Br J Rheumatol 1994; 33: 735–739.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. MacGregor AJ, Bamder S, Silman AJ . A comparison of the performance of different methods of disease classification for rheumatoid arthritis. Results from an analysis from a nationwide twin study. J Rheumatol 1994; 21: 1420–1426.

    CAS  PubMed  Google Scholar 

  22. Bukhari M, Harrison B, Lunt M, Scott DG, Symmons DP, Silman AJ . Time to first occurrence of erosions in inflammatory polyarthritis: results from a prospective community-based study. Arthritis Rheum 2001; 44: 1248–1253.

    Article  CAS  Google Scholar 

  23. Larsen A, Dale K, Eek M . Radiographic evaluation of rheumatoid arthritis and related conditions by standard reference films. Ada Radiol Diagn (Stockh) 1977; 18: 481–491.

    CAS  Google Scholar 

  24. Bukhari M, Lunt M, Harrison BJ, Scott DG, Symmons DP, Silman AJ . Rheumatoid factor is the major predictor of increasing severity of radiographic erosions in rheumatoid arthritis: results from the Norfolk Arthritis Register Study, a large inception cohort. Arthritis Rheum 2002; 46: 906–912.

    Article  CAS  Google Scholar 

  25. Curtis D, Sham PC . Model-free linkage analysis using likelihoods. Am J Hum Genet 1995; 57: 703–716.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Arthritis Rheumatism Campaign Epidemiology Research Unit, University of Manchester, Manchester, UK

    A Barton, R Lamb, D Symmons, A Silman, W Thomson, J Worthington & R Donn

Authors
  1. A Barton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Lamb
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D Symmons
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Silman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. W Thomson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Worthington
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R Donn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Barton.

Additional information

Funding: Arthritis Research Campaign

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barton, A., Lamb, R., Symmons, D. et al. Macrophage migration inhibitory factor (MIF) gene polymorphism is associated with susceptibility to but not severity of inflammatory polyarthritis. Genes Immun 4, 487–491 (2003). https://doi.org/10.1038/sj.gene.6364014

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6364014

Keywords

This article is cited by

Search

Advanced search

Quick links