RGMA and IL21R show association with experimental inflammation and multiple sclerosis

• Published in: Genes and immunity Vol. 11; no. 4; pp. 279 - 293
• Main Authors: Nohra, R, Beyeen, A D, Guo, J P, Khademi, M, Sundqvist, E, Hedreul, M T, Sellebjerg, F, Smestad, C, Oturai, A B, Harbo, H F, Wallström, E, Hillert, J, Alfredsson, L, Kockum, I, Jagodic, M, Lorentzen, J, Olsson, T
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-06-2010; Nature Publishing Group
• Subjects: 631/208/205; 631/208/729/743; 692/308/1426; 692/699/249/1313; Animal models; Animals; Antibodies; Antigens; Arthritis; Autoimmune diseases; Biomarkers; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cerebrospinal fluid; Chromosome 1; Chromosomes; Cytokines; Development and progression; Diabetes; Encephalomyelitis; Encephalomyelitis, Autoimmune, Experimental - genetics; Experimental allergic encephalomyelitis; Female; g-Interferon; Gene Expression; Genes; Genetic aspects; Genetic Linkage; Haplotypes; Hospitals; Human Genetics; Immunology; Inflammation; Inflammatory diseases; Interleukin 4 receptors; Interleukin 6; Leukocytes; Leukocytes (mononuclear); Male; Medicin och hälsovetenskap; Membrane Proteins - genetics; Multiple sclerosis; Multiple Sclerosis - genetics; Myelin; Nerve Tissue Proteins - genetics; Neurology; Neurosciences; Oligodendrocyte-myelin glycoprotein; original-article; Peripheral blood mononuclear cells; Physiological aspects; Polymorphism, Single Nucleotide; Pristane; Quantitative Trait Loci; Rats; Receptors, Interleukin-21 - genetics; Risk factors; Single-nucleotide polymorphism; Therapeutic targets; Tumor necrosis factor; Tumor necrosis factor-TNF; γ-Interferon; Sweden; Norway; autoimmunity; multiple sclerosis; experimental autoimmune encephalomyelitis
• ISSN: 1466-4879; 1476-5470; 1476-5470
• DOI: 10.1038/gene.2009.111

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-γ (IFN-γ) 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-γ 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.