title: Correlation of rheumatoid arthritis severity with the genetic functional variants and circulating levels of macrophage migration inhibitory factor.
abstract: OBJECTIVE
  To study whether genetic variants of macrophage migration inhibitory factor (MIF), the MIF -173G>C and CATT(5-8) alleles, are associated with disease severity and levels of circulating MIF in patients with rheumatoid arthritis (RA).
  
  
  METHODS
  Genotyping was performed in patients with early RA and in healthy controls. Demographic data, disease activity, and outcome measurements were compared between patients with and without the MIF variants. MIF -173G>C and CATT(5-8) polymorphisms were genotyped, and a newly developed enzyme-linked immunosorbent assay for human MIF was used. Allele and genotype distributions of the MIF -173G>C and CATT(5-8) polymorphisms were compared between patients and controls by chi-square test. Multiple regression analysis was performed to assess the independence of the MIF functional genetic variants as risk factors for radiologic joint damage.
  
  
  RESULTS
  Genotyping of the -173G>C and CATT(5-8) polymorphisms of MIF in RA patients and healthy individuals (n = 277 each) revealed similar frequencies of genotypes and haplotypes in both groups. No significant differences in demographic or clinical features were observed between RA patients carrying the MIF -173C allele or the MIF CATT7 allele or both and non-carrier RA patients. Radiologic joint damage was significantly higher in patients carrying risk alleles of the MIF -173G>C or the MIF CATT(5-8) functional variants. No synergistic effects between both genetic variants were observed. Multivariate regression analysis revealed that presence of the MIF -173C/C and MIF CATT(7/7) genotypes and having 1 MIF -173C allele were independent prognostic variables. Carriership of the MIF -173C allele (P = 0.002) or MIF CATT7 allele (P = 0.004) was associated with significantly higher circulating MIF levels compared with those in subjects having none of the risk-conferring alleles, and greater circulating MIF levels correlated with more severe radiologic joint damage (r = 0.64, P = 0.001).
  
  
  CONCLUSIONS
  The MIF polymorphisms are not associated with RA susceptibility but are associated with high levels of radiologic joint damage. High circulating MIF levels were shown to correlate strongly with radiologic joint damage, suggesting that MIF expression is genetically determined and can be used as a novel prognostic tool in RA.
authors.affiliation: Department of Rheumatology, Experimental Rheumatology and Advanced Therapeutics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. T.Radstake@reuma.umcn.nl
authors.forename: Timothy R D J
authors.initials: TR
authors.lastname: Radstake
authors.forename: Fred C G J
authors.initials: FC
authors.lastname: Sweep
authors.forename: Paco
authors.initials: P
authors.lastname: Welsing
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.forename: Sita H H M
authors.initials: SH
authors.lastname: Vermeulen
authors.forename: Anneke
authors.initials: A
authors.lastname: Geurts-Moespot
authors.forename: Thierry
authors.initials: T
authors.lastname: Calandra
authors.forename: Rachelle
authors.initials: R
authors.lastname: Donn
authors.forename: Piet L C M
authors.initials: PL
authors.lastname: van Riel
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000175:diagnosis* / Q000235:genetics*; D015415:Biomarkers; D005260:Female; D005819:Genetic Markers; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007596:Joints / Q000473:pathology; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011379:Prognosis; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; D005819:Genetic Markers; D008263:Macrophage Migration-Inhibitory Factors