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A functional promoter polymorphism in the macrophage migration inhibitory factor (MIF) gene associated with disease severity in rheumatoid arthritis

Genes & Immunity volume 3, pages 170–176 (2002)Cite this article

Abstract

The macrophage migration inhibitory factor (MIF) is a potent pro-inflammatory cytokine and regulates the anti-inflammator effects of glucocorticoids. An important role for MIF within the cytokine cascade is to act in concert with endogenous glucocorticoids to control the set-point and magnitude of the inflammatory response. Elevated expression of MIF in the circulation and in the synovial joint has been documented in rheumatoid arthritis. MIF also has been linked to the development of joint damage and disease pathology in experimental animal models. We describe herein a novel CATT-tetranucleotide repeat polymorphism at position −794 of the human Mif gene and show that it functionally affects the activity of the MIF promoter in gene reporter assays. We describe four genotypes which comprise 5, 6, 7, or 8-CATT repeat units and show that the 5-CATT allele has the lowest level of basal and stimulated MIF promoter activity in vitro. The presence of the low expressing, 5-CATT repeat allele correlated with low disease severity in a cohort of rheumatoid arthritis patients.

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Author notes

  1. J A Baugh and S Chitnis: These authors contributed equally to this work; SC originally identified the MIF-CATT polymorphism and performed population studies.

Authors and Affiliations

  1. Laboratory of Medical Biochemistry, The Picower Institute for Medical Research, 350 Community Drive, Manhasset, 11030, NY, USA

    J A Baugh, S C Donnelly, X Lin & R Bucala

  2. Center for Genomics and Human Genetics, North Shore Long Island Jewish Research Institute, 350 Community Drive, Manhasset, 11030, NY, USA

    S Chitnis, J Monteiro & P K Gregersen

  3. Department Medicine & Therapeutics, Conway Institute, St. Vincent’s Hospital, Elm Park, Dublin, 4, Ireland

    S C Donnelly & B J Plant

  4. Arthritis Research Center, Wichita, Kansas, 67214, MO, USA

    F Wolfe

Authors
  1. J A Baugh
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  2. S Chitnis
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  3. S C Donnelly
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  4. J Monteiro
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  5. X Lin
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  6. B J Plant
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  7. F Wolfe
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  8. P K Gregersen
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  9. R Bucala
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Corresponding authors

Correspondence to P K Gregersen or R Bucala.

Additional information

The authors would like to acknowledge support form the NIH (RB – 1R01-AI35931, 1R01-AI42310; PKG – RO1-AR44222), The Wellcome Trust, and The Picower Institute for Medical Research. We also thank Ms Nina Kohn for expert assistance with biostatistical analysis.

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Baugh, J., Chitnis, S., Donnelly, S. et al. A functional promoter polymorphism in the macrophage migration inhibitory factor (MIF) gene associated with disease severity in rheumatoid arthritis. Genes Immun 3, 170–176 (2002). https://doi.org/10.1038/sj.gene.6363867

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  • DOI: https://doi.org/10.1038/sj.gene.6363867

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