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 Sep;46(9):2402-9. doi: 10.1002/art.10492.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Arthritis, Juvenile / blood
  • Arthritis, Juvenile / genetics*
  • Cell Line
  • DNA Mutational Analysis*
  • Gene Frequency
  • Genes, Reporter
  • Genetic Predisposition to Disease
  • Genetic Testing*
  • Genotype
  • Humans
  • Macrophage Migration-Inhibitory Factors / blood
  • Macrophage Migration-Inhibitory Factors / genetics*
  • Microsatellite Repeats
  • Polymorphism, Genetic*
  • Reference Values
  • Transfection

Substances

  • Macrophage Migration-Inhibitory Factors