1. Genes Immun. 2010 Jun;11(4):279-93. doi: 10.1038/gene.2009.111. Epub 2010 Jan 14.
RGMA and IL21R show association with experimental inflammation and multiple
sclerosis.
Nohra R(1), Beyeen AD, Guo JP, Khademi M, Sundqvist E, Hedreul MT, Sellebjerg F,
Smestad C, Oturai AB, Harbo HF, Wallström E, Hillert J, Alfredsson L, Kockum I,
Jagodic M, Lorentzen J, Olsson T.
Author information:
(1)Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska
Institutet, Stockholm, Sweden. rita.nohra@ki.se
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-gamma 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.
PMID: 20072140 [PubMed - indexed for MEDLINE]
PUBMED: 20072140
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