title: Macrophage migration inhibitory factor promoter polymorphisms and the clinical expression of scleroderma.
abstract: OBJECTIVE
  To investigate the potential association between functional polymorphisms in the gene for the innate mediator, macrophage migration inhibitory factor (MIF), and the clinical expression of systemic sclerosis (SSc).
  
  
  METHODS
  Genomic DNA samples and clinical data were collected from the Scleroderma Family Registry and DNA Repository at the University of Texas Health Science Center at Houston. A total of 740 subjects were studied; 203 of them had diffuse cutaneous SSc (dcSSc), 283 had limited cutaneous SSc (lcSSc), and the remaining 254 healthy subjects served as controls. Association analyses were performed on the whole data set and on patient and sex subsets. Significant relationships were determined between clinical variables and MIF polymorphisms for each disease subtype in the studied groups.
  
  
  RESULTS
  The frequency of the -173*C MIF allele, which was previously reported to be associated with high production of MIF, was lower in the lcSSc group (12.6%) than in the dcSSc (19.2%) or control (18.5%) groups (P = 0.010 and P = 0.011, respectively). Haplotype analysis for 2 closely linked polymorphisms in the MIF promoter showed that in white subjects with lcSSc or dcSSc, the lcSSc population had a significantly lower representation of the high-expression MIF haplotype defined by -173*C and -794 with 7 CATT repeats (C7) (P = 0.015, odds ratio 1.94 [95% confidence interval 1.14-3.32]). Fibroblasts encoding the C7 MIF haplotype were observed to produce more MIF upon in vitro stimulation than those with a non-C7 haplotype.
  
  
  CONCLUSIONS
  Functional promoter polymorphisms in the MIF gene affect the clinical presentation of SSc. The proinflammatory haplotype defined by C7 is underrepresented in patients with lcSSc.
authors.affiliation: Yale University School of Medicine, New Haven, Connecticut 06520-8031, USA.
authors.forename: Sou-Pan
authors.initials: SP
authors.lastname: Wu
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.forename: Zeny
authors.initials: Z
authors.lastname: Feng
authors.forename: Nianjun
authors.initials: N
authors.lastname: Liu
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.forename: Courtney
authors.initials: C
authors.lastname: McDonald
authors.forename: Annette
authors.initials: A
authors.lastname: Lee
authors.forename: Frank C
authors.initials: FC
authors.lastname: Arnett
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Maureen D
authors.initials: MD
authors.lastname: Mayes
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
mesh_terms: D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000276:immunology; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D012042:Registries; D012091:Repetitive Sequences, Nucleic Acid; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D012867:Skin / Q000166:cytology / Q000276:immunology
chemical_list: D008263:Macrophage Migration-Inhibitory Factors