Journal
GENES AND IMMUNITY
Volume 11, Issue 4, Pages 279-293Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gene.2009.111
Keywords
multiple sclerosis; experimental autoimmune encephalomyelitis; autoimmunity; RGMA; IL21R
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Funding
- Swedish Research council
- Swedish foundation for neurologically handicapped (NHR)
- Bibbi and Nils Jensens Foundation
- Montel Williams Foundation
- Soderbergs Foundation
- EU [LSHM-CT-2005-018637, LSHG-CT-2005-019015]
- Norwegian Foundation for Health and Rehabilitation [2004/2/0125]
- Odd Fellow MS society, Norway
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Rat chromosome 1 harbors overlapping quantitative trait loci (QTL) for cytokine production and experimental models of inflammatory diseases. We fine-dissected this region that regulated cytokine production, myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), anti-MOG antibodies and pristane-induced arthritis (PIA) in advanced intercross lines (AILs). Analysis in the tenth and twelfth generation of AILs resolved the region in two narrow QTL, Eae30 and Eae31. Eae30 showed linkage to MOG-EAE, anti-MOG antibodies and levels of interleukin-6 (IL-6). Eae31 showed linkage to EAE, PIA, anti-MOG antibodies and levels of tumor necrosis factor (TNF) and IL-6. Confidence intervals defined a limited set of potential candidate genes, with the most interesting being RGMA, IL21R and IL4R. We tested the association with multiple sclerosis (MS) in a Nordic case-control material. A single nucleotide polymorphism in RGMA associated with MS in males (odds ratio (OR) = 1.33). Polymorphisms of RGMA also correlated with changes in the expression of interferon-gamma (IFN-gamma) and TNF in cerebrospinal fluid of MS patients. In IL21R, there was one positively associated (OR = 1.14) and two protective (OR = 0.87 and 0.68) haplotypes. One of the protective haplotypes correlated to lower IFN-g expression in peripheral blood mononuclear cells of MS patients. We conclude that RGMA and IL21R and their pathways are crucial in MS pathogenesis and warrant further studies as potential biomarkers and therapeutic targets. Genes and Immunity (2010) 11, 279-293; doi:10.1038/gene.2009.111; published online 14 January 2010
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