Macrophage migration inhibitory factor promoter polymorphisms and the clinical expression of scleroderma.
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.
Wu
Sou-Pan
SP
Yale University School of Medicine, New Haven, Connecticut 06520-8031, USA.
Leng
Lin
L
Feng
Zeny
Z
Liu
Nianjun
N
Zhao
Hongyu
H
McDonald
Courtney
C
Lee
Annette
A
Arnett
Frank C
FC
Gregersen
Peter K
PK
Mayes
Maureen D
MD
Bucala
Richard
R
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
D008263:Macrophage Migration-Inhibitory Factors