Mutation screening of the macrophage migration inhibitory factor gene

Positive association of a functional polymorphism of macrophage migration inhibitory factor with juvenile idiopathic arthritis

Rachelle Donn, Zaynab Alourfi, Fabrizio De Benedetti, Cristina Meazza, Eleftheria Zeggini, Mark Lunt, Adam Stevens, Emma Shelley, Rebecca Lamb, William E R Ollier, Wendy Thomson, David Ray, M. Abinun, M. Becker, A. Bell, A. Craft, E. Crawley, J. David, H. Foster, J. Gardener-Medwin & 15 others J. Griffin, A. Hall, M. Hall, A. Herrick, P. Hollingworth, L. Holt, S. Jones, G. Pountain, C. Ryder, T. Southwood, I. Stewart, H. Venning, L. Wedderburn, P. Woo, S. Wyatt

Research output: Contribution to journalArticle

208 Citations (Scopus)

Abstract

Objective. To determine if polymorphisms of the macrophage migration inhibitory factor (MIF) gene are associated with juvenile idiopathic arthritis (JIA). Methods. Denaturing high-performance liquid chromatography was used to screen the MIF gene in 32 UK Caucasian controls and 88 UK Caucasian JIA patients. Ninety-two healthy UK Caucasian controls were then genotyped for each of the polymorphic positions identified. A panel of 526 UK Caucasian JIA patients and 259 UK Caucasian controls were subsequently genotyped for a single-nucleotide polymorphism (SNP) identified in the 5′-flanking region of the gene, using SNaPshot ddNTP primer extension and capillary electrophoresis. The functional significance of this polymorphism was also studied using luciferase-based reporter gene assays in human T lymphoblast and epithelial cell lines. Results. A tetranucleotide repeat CATT(5-7) beginning at nucleotide position -794 and 3 SNPs at positions -173 (G to C), +254 (T to C), and +656 (C to G) of the MIF gene were identified. No JIA-specific mutations were found. Allele and genotype frequencies differed significantly between the controls and the JIA patients for the MIF-173 polymorphism. Individuals possessing a MIF-173*C allele had an increased risk of JIA (34.8% versus 21.6%) (odds ratio 1.9, 95% confidence interval 1.4-2.7; P = 0.0002). Furthermore, the MIF-173* G and C variants resulted in altered expression of MIF in a cell type-specific manner. Serum levels of MIF were also significantly higher in individuals who carried a MIF-173*C allele (P = 0.04). Conclusion. The -173-MIF*C allele confers increased risk of susceptibility to JIA. Our data suggest a cell type-specific regulation of MIF, which may be central to understanding its role in inflammation.

Original languageEnglish
Pages (from-to)2402-2409
Number of pages8
JournalArthritis and Rheumatism
Volume46
Issue number9
DOIs
Publication statusPublished - Sep 1 2002

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Macrophage Migration-Inhibitory Factors
Juvenile Arthritis
Mutation
Genes
Alleles
Single Nucleotide Polymorphism
Dideoxynucleotides
5' Flanking Region
Capillary Electrophoresis
Luciferases
Reporter Genes
Gene Frequency
Microsatellite Repeats
Nucleotides
Epithelial Cells
Odds Ratio
Genotype
High Pressure Liquid Chromatography
Confidence Intervals
Inflammation

ASJC Scopus subject areas

  • Immunology
  • Rheumatology

Cite this

Mutation screening of the macrophage migration inhibitory factor gene : Positive association of a functional polymorphism of macrophage migration inhibitory factor with juvenile idiopathic arthritis. / Donn, Rachelle; Alourfi, Zaynab; De Benedetti, Fabrizio; Meazza, Cristina; Zeggini, Eleftheria; Lunt, Mark; Stevens, Adam; Shelley, Emma; Lamb, Rebecca; Ollier, William E R; Thomson, Wendy; Ray, David; Abinun, M.; Becker, M.; Bell, A.; Craft, A.; Crawley, E.; David, J.; Foster, H.; Gardener-Medwin, J.; Griffin, J.; Hall, A.; Hall, M.; Herrick, A.; Hollingworth, P.; Holt, L.; Jones, S.; Pountain, G.; Ryder, C.; Southwood, T.; Stewart, I.; Venning, H.; Wedderburn, L.; Woo, P.; Wyatt, S.

In: Arthritis and Rheumatism, Vol. 46, No. 9, 01.09.2002, p. 2402-2409.

Research output: Contribution to journalArticle

Donn, R, Alourfi, Z, De Benedetti, F, Meazza, C, Zeggini, E, Lunt, M, Stevens, A, Shelley, E, Lamb, R, Ollier, WER, Thomson, W, Ray, D, Abinun, M, Becker, M, Bell, A, Craft, A, Crawley, E, David, J, Foster, H, Gardener-Medwin, J, Griffin, J, Hall, A, Hall, M, Herrick, A, Hollingworth, P, Holt, L, Jones, S, Pountain, G, Ryder, C, Southwood, T, Stewart, I, Venning, H, Wedderburn, L, Woo, P & Wyatt, S 2002, '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 and Rheumatism, vol. 46, no. 9, pp. 2402-2409. https://doi.org/10.1002/art.10492
Donn, Rachelle ; Alourfi, Zaynab ; De Benedetti, Fabrizio ; Meazza, Cristina ; Zeggini, Eleftheria ; Lunt, Mark ; Stevens, Adam ; Shelley, Emma ; Lamb, Rebecca ; Ollier, William E R ; Thomson, Wendy ; Ray, David ; Abinun, M. ; Becker, M. ; Bell, A. ; Craft, A. ; Crawley, E. ; David, J. ; Foster, H. ; Gardener-Medwin, J. ; Griffin, J. ; Hall, A. ; Hall, M. ; Herrick, A. ; Hollingworth, P. ; Holt, L. ; Jones, S. ; Pountain, G. ; Ryder, C. ; Southwood, T. ; Stewart, I. ; Venning, H. ; Wedderburn, L. ; Woo, P. ; Wyatt, S. / Mutation screening of the macrophage migration inhibitory factor gene : Positive association of a functional polymorphism of macrophage migration inhibitory factor with juvenile idiopathic arthritis. In: Arthritis and Rheumatism. 2002 ; Vol. 46, No. 9. pp. 2402-2409.
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abstract = "Objective. To determine if polymorphisms of the macrophage migration inhibitory factor (MIF) gene are associated with juvenile idiopathic arthritis (JIA). Methods. Denaturing high-performance liquid chromatography was used to screen the MIF gene in 32 UK Caucasian controls and 88 UK Caucasian JIA patients. Ninety-two healthy UK Caucasian controls were then genotyped for each of the polymorphic positions identified. A panel of 526 UK Caucasian JIA patients and 259 UK Caucasian controls were subsequently genotyped for a single-nucleotide polymorphism (SNP) identified in the 5′-flanking region of the gene, using SNaPshot ddNTP primer extension and capillary electrophoresis. The functional significance of this polymorphism was also studied using luciferase-based reporter gene assays in human T lymphoblast and epithelial cell lines. Results. A tetranucleotide repeat CATT(5-7) beginning at nucleotide position -794 and 3 SNPs at positions -173 (G to C), +254 (T to C), and +656 (C to G) of the MIF gene were identified. No JIA-specific mutations were found. Allele and genotype frequencies differed significantly between the controls and the JIA patients for the MIF-173 polymorphism. Individuals possessing a MIF-173*C allele had an increased risk of JIA (34.8{\%} versus 21.6{\%}) (odds ratio 1.9, 95{\%} confidence interval 1.4-2.7; P = 0.0002). Furthermore, the MIF-173* G and C variants resulted in altered expression of MIF in a cell type-specific manner. Serum levels of MIF were also significantly higher in individuals who carried a MIF-173*C allele (P = 0.04). Conclusion. The -173-MIF*C allele confers increased risk of susceptibility to JIA. Our data suggest a cell type-specific regulation of MIF, which may be central to understanding its role in inflammation.",
author = "Rachelle Donn and Zaynab Alourfi and {De Benedetti}, Fabrizio and Cristina Meazza and Eleftheria Zeggini and Mark Lunt and Adam Stevens and Emma Shelley and Rebecca Lamb and Ollier, {William E R} and Wendy Thomson and David Ray and M. Abinun and M. Becker and A. Bell and A. Craft and E. Crawley and J. David and H. Foster and J. Gardener-Medwin and J. Griffin and A. Hall and M. Hall and A. Herrick and P. Hollingworth and L. Holt and S. Jones and G. Pountain and C. Ryder and T. Southwood and I. Stewart and H. Venning and L. Wedderburn and P. Woo and S. Wyatt",
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AU - Alourfi, Zaynab

AU - De Benedetti, Fabrizio

AU - Meazza, Cristina

AU - Zeggini, Eleftheria

AU - Lunt, Mark

AU - Stevens, Adam

AU - Shelley, Emma

AU - Lamb, Rebecca

AU - Ollier, William E R

AU - Thomson, Wendy

AU - Ray, David

AU - Abinun, M.

AU - Becker, M.

AU - Bell, A.

AU - Craft, A.

AU - Crawley, E.

AU - David, J.

AU - Foster, H.

AU - Gardener-Medwin, J.

AU - Griffin, J.

AU - Hall, A.

AU - Hall, M.

AU - Herrick, A.

AU - Hollingworth, P.

AU - Holt, L.

AU - Jones, S.

AU - Pountain, G.

AU - Ryder, C.

AU - Southwood, T.

AU - Stewart, I.

AU - Venning, H.

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