RGD Reference Report - A role for VAV1 in experimental autoimmune encephalomyelitis and multiple sclerosis. - Rat Genome Database

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A role for VAV1 in experimental autoimmune encephalomyelitis and multiple sclerosis.

Authors: Jagodic, M  Colacios, C  Nohra, R  Dejean, AS  Beyeen, AD  Khademi, M  Casemayou, A  Lamouroux, L  Duthoit, C  Papapietro, O  Sjoholm, L  Bernard, I  Lagrange, D  Dahlman, I  Lundmark, F  Oturai, AB  Soendergaard, HB  Kemppinen, A  Saarela, J  Tienari, PJ  Harbo, HF  Spurkland, A  Ramagopalan, SV  Sadovnick, DA  Ebers, GC  Seddighzadeh, M  Klareskog, L  Alfredsson, L  Padyukov, L  Hillert, J  Clanet, M  Edan, G  Fontaine, B  Fournie, GJ  Kockum, I  Saoudi, A  Olsson, T 
Citation: Jagodic M, etal., Sci Transl Med. 2009 Dec 9;1(10):10ra21. doi: 10.1126/scitranslmed.3000278.
RGD ID: 7241236
Pubmed: PMID:20368159   (View Abstract at PubMed)
DOI: DOI:10.1126/scitranslmed.3000278   (Journal Full-text)

Multiple sclerosis, the most common cause of progressive neurological disability in young adults, is a chronic inflammatory disease. There is solid evidence for a genetic influence in multiple sclerosis, and deciphering the causative genes could reveal key pathways influencing the disease. A genome region on rat chromosome 9 regulates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. Using interval-specific congenic rat lines and association of single-nucleotide polymorphisms with inflammatory phenotypes, we localized the gene of influence to Vav1, which codes for a signal-transducing protein in leukocytes. Analysis of seven human cohorts (12,735 individuals) demonstrated an association of rs2546133-rs2617822 haplotypes in the first VAV1 intron with multiple sclerosis (CA: odds ratio, 1.18; CG: odds ratio, 0.86; TG: odds ratio, 0.90). The risk CA haplotype also predisposed for higher VAV1 messenger RNA expression. VAV1 expression was increased in individuals with multiple sclerosis and correlated with tumor necrosis factor and interferon-gamma expression in peripheral blood and cerebrospinal fluid cells. We conclude that VAV1 plays a central role in controlling central nervous system immune-mediated disease and proinflammatory cytokine production critical for disease pathogenesis.



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Strain DA.BN-(D9Got8-D9Rat139)/Kini null Rattus norvegicus
Strain DA.BN-(D9Wox18-D9Rat20)/Kini null Rattus norvegicus
QTL Eae4 Experimental allergic encephalomyelitis QTL 4 Rattus norvegicus

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