A functional promoter haplotype of macrophage migration inhibitory factor is linked and associated with juvenile idiopathic arthritis.
OBJECTIVE
To establish linkage and replicate the association of macrophage migration inhibitory factor (MIF) with juvenile idiopathic arthritis (JIA).


METHODS
Three hundred twenty-one Caucasian simplex families from the UK were genotyped for polymorphisms of MIF using SNaPshot ddNTP primer extension, or by a fluorescently labeled primer method, and capillary gel electrophoresis. The functional significance of the promoter polymorphisms was studied using luciferase-based reporter gene assays in human T lymphoblast and epithelial cell lines.


RESULTS
MIF was linked and associated with JIA (P = 0.0016). Specifically, a 2-point promoter haplotype, CATT(7)-MIF-173*C, was found to be transmitted in excess (38 transmitted: 21 not transmitted) in the JIA patients. Conditional extended transmission disequilibrium test and pairwise extended transmission disequilibrium test predicted functional interaction between the 2 polymorphic positions. The interaction of the CATT repeat with MIF-173*G/C was found to be specific to the cell type.


CONCLUSIONS
Replication of an association and linkage of MIF with JIA has been established. Functional interaction between the polymorphic positions on the linked haplotype has also been shown. The molecular mechanism of this interaction is currently being investigated.
Donn
Rachelle
R
Arthritis Research Campaign/Epidemiology Unit, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK. Rachelle@fs1.ser.man.ac.uk
Alourfi
Zaynab
Z
Zeggini
Eleftheria
E
Lamb
Rebecca
R
Jury
Francine
F
Lunt
Mark
M
Meazza
Christina
C
De Benedetti
Fabrizio
F
Thomson
Wendy
W
Ray
David
D
D001171:Arthritis, Juvenile / Q000097:blood / Q000235:genetics*; D002097:C-Reactive Protein / Q000378:metabolism; D002460:Cell Line; D017930:Genes, Reporter; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D020545:Respiratory Mucosa / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology; D014162:Transfection
D008263:Macrophage Migration-Inhibitory Factors; D002097:C-Reactive Protein