title: A genetic role for macrophage migration inhibitory factor (MIF) in adult-onset Still's disease.
abstract: BACKGROUND
  Adult-onset still's disease (AOSD) is a rare systemic inflammatory disorder in which abnormalities in inflammatory cytokines production appear to play a pathophysiological role. Our previous work has reported increased expression of macrophage migration inhibitory factor (MIF) and revealed its correlation with disease severity and activity in AOSD. A -173 G/C single nucleotide polymorphism (SNP) (rs755622) and a -794 CATT₅₋₈ repeat (rs5844572) in the MIF promoter have been reported. In this study, we sought to explore the relationship between functional MIF promoter polymorphisms and MIF expression in AOSD.
  
  
  METHODS
  100 patients and 200 controls were recruited in the study. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was utilized to analyze the -173 G/C SNP (rs755622) and PCR-based size discrimination assay was applied to detect the -794 CATT₅₋₈ repeat (rs5844572) in the MIF promoter. Plasma MIF levels were measured by ELISA. MIF mRNA levels were quantified by real-time reverse transcription (RT)-PCR. Bisulfate genomic sequencing was employed to evaluate DNA methylation status within the MIF promoter.
  
  
  RESULTS
  We identified that the frequencies of MIF -794 CATT₅ (P = 0.001) allele and the expression of MIF (P <0.001) were increased in patients compared to healthy controls. Plasma levels of MIF in patients with CC genotype were higher than those of patients with GC or GG genotypes (P = 0.05). In patients with established AOSD, a higher frequency of -794 CATT₇ containing MIF genotypes was observed in those with liver dysfunction (P = 0.009). Haplotype analysis revealed a higher representation of the MIF haplotype defined by -173*C/-794 CATT₅ (C5) in AOSD patients (P = 0.001).
  
  
  CONCLUSIONS
  Functional promoter polymorphisms in the MIF gene influence plasma MIF levels in AOSD and may contribute to disease susceptibility or clinical presentation of AOSD.
authors.forename: Fang-Fang
authors.initials: FF
authors.lastname: Wang
authors.forename: Xin-Fang
authors.initials: XF
authors.lastname: Huang
authors.forename: Nan
authors.initials: N
authors.lastname: Shen
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Shun-Le
authors.initials: SL
authors.lastname: Chen
authors.forename: Liang-Jing
authors.initials: LJ
authors.lastname: Lu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019175:DNA Methylation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000097:blood / Q000235:genetics*; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016706:Still's Disease, Adult-Onset / Q000097:blood / Q000235:genetics*; D055815:Young Adult
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human