Mutation screening of the macrophage migration inhibitory factor gene - Positive association of a functional polymorphism of macrophage migration inhibitory factor with juvenile idiopathic arthritis

被引:224
作者
Donn, R
Alourfi, Z
De Benedetti, F
Meazza, C
Zeggini, E
Lunt, M
Stevens, A
Shelley, E
Lamb, R
Ollier, WER
Thomson, W
Ray, D
机构
[1] Univ Manchester, Epidemiol Unit, Arthrit Res Campaign, Manchester M13 9PT, Lancs, England
[2] Univ Manchester, Endocrine Sci Res Unit, Manchester, Lancs, England
[3] Policlin San Matteo, Pavia, Italy
来源
ARTHRITIS AND RHEUMATISM | 2002年 / 46卷 / 09期
关键词
D O I
10.1002/art.10492
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective. To determine if polymorphisms of the macrophage migration inhibitory factor (MIF) gene are associated with juvenile idiopathic arthritis (JIA). Methods. Denaturing high-performance liquid chromatography was used to screen the MIF gene in 32 UK Caucasian controls and 88 UK Caucasian JIA patients. Ninety-two healthy UK Caucasian controls were then genotyped for each of the polymorphic positions identified. A panel of 526 UK Caucasian JIA patients and 259 UK Caucasian controls were subsequently genotyped for a single-nucleotide polymorphism (SNP) identified in the 5'-flanking region of the gene, using SNaPshot ddNTP primer extension and capillary electrophoresis. The functional significance of this polymorphism was also studied using luciferase-based reporter gene assays in human T lymphoblast and epithelial cell lines. Results. A tetranucleotide repeat CATT((5-7)) beginning at nucleotide position -794 and 3 SNPs at positions -173 (G to C), +254 (T to C), and +656 (C to G) of the MIF gene were identified. No JIA-specific mutations were found. Allele and genotype frequencies differed significantly between the controls and the RA patients for the MIF-173 polymorphism. Individuals possessing a MIF-173*C allele had an increased risk of JIA (34.8% versus 21.6%) (odds ratio 1.9, 95% confidence interval 1.4-2.7; P = 0.0002). Furthermore, the MIF-173* G and C variants resulted in altered expression of MIF in a cell type-specific manner. Serum levels of MIF were also significantly higher in individuals who carried a MIF-173*C allele (P = 0.04). Conclusion. The -173-MIF*C allele confers increased risk of susceptibility to JIA. Our data suggest a cell type-specific regulation of MIF, which may be central to understanding its role in inflammation.
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收藏
页码:2402 / 2409
页数:8
相关论文
共 44 条
[31]   CLONING THE HUMAN GENE FOR MACROPHAGE-MIGRATION INHIBITORY FACTOR (MIF) [J].
PARALKAR, V ;
WISTOW, C .
GENOMICS, 1994, 19 (01) :48-51
[32]  
Petty Ross E., 1998, Journal of Rheumatology, V25, P1991
[33]   MatInd and MatInspector: New fast and versatile tools for detection of consensus matches in nucleotide sequence data [J].
Quandt, K ;
Frech, K ;
Karas, H ;
Wingender, E ;
Werner, T .
NUCLEIC ACIDS RESEARCH, 1995, 23 (23) :4878-4884
[34]   Leukemia inhibitory factor (LIF) stimulates proopiomelanocortin (POMC) expression in a corticotroph cell line - Role of STAT pathway [J].
Ray, DW ;
Ren, SG ;
Melmed, S .
JOURNAL OF CLINICAL INVESTIGATION, 1996, 97 (08) :1852-1859
[35]   Human uveal melanoma cells produce macrophage migration-inhibitory factor to prevent lysis by NK cells [J].
Repp, AC ;
Mayhew, ES ;
Apte, S ;
Niederkorn, JY .
JOURNAL OF IMMUNOLOGY, 2000, 165 (02) :710-715
[36]   MIF regulates innate immune responses through modulation of Toll-like receptor 4 [J].
Roger, T ;
David, J ;
Glauser, MP ;
Calandra, T .
NATURE, 2001, 414 (6866) :920-924
[37]  
Sampey AV, 2001, ARTHRITIS RHEUM-US, V44, P1273, DOI 10.1002/1529-0131(200106)44:6<1273::AID-ART219>3.0.CO
[38]  
2-8
[39]   Role of macrophage migration inhibitory factor (MIF) in murine antigen-induced arthritis: interaction with glucocorticoids [J].
Santos, L ;
Hall, P ;
Metz, C ;
Bucala, R ;
Morand, EF .
CLINICAL AND EXPERIMENTAL IMMUNOLOGY, 2001, 123 (02) :309-314
[40]   High macrophage migration inhibitory factor (MIF) serum levels associated with extended psoriasis [J].
Shimizu, T ;
Nishihira, J ;
Mizue, Y ;
Nakamura, H ;
Abe, R ;
Watanabe, H ;
Ohkawara, A ;
Shimizu, H .
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2001, 116 (06) :989-990