1. A role for VAV1 in experimental autoimmune encephalomyelitis and multiple sclerosis
- Author
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Audrey Casemayou, Anu Kemppinen, Lucille Lamouroux, Pentti J. Tienari, Gilbert J. Fournié, Ingrid Dahlman, Ingrid Kockum, Olivier Papapietro, Rita Nohra, Lars Klareskog, Gilles Edan, George C. Ebers, Annette Bang Oturai, Louise K. Sjöholm, Dominique Lagrange, Michel Clanet, Mohsen Khademi, Anne Spurkland, Céline Colacios, Frida Lundmark, Leonid Padyukov, Helle Bach Soendergaard, Christine Duthoit, Abdelhadi Saoudi, Amennai Daniel Beyeen, Isabelle Bernard, Tomas Olsson, Anne Dejean, Dessa Sadovnick, Maja Jagodic, Maria Seddighzadeh, Jan Hillert, Janna Saarela, Bertrand Fontaine, Hanne F. Harbo, Sreeram V. Ramagopalan, and Lars Alfredsson
- Subjects
CD4-Positive T-Lymphocytes ,Encephalomyelitis, Autoimmune, Experimental ,Multiple Sclerosis ,Tumor Necrosis Factor-alpha ,Multiple sclerosis ,Central nervous system ,Experimental autoimmune encephalomyelitis ,Haplotype ,Quantitative Trait Loci ,Congenic ,Genome-wide association study ,General Medicine ,Odds ratio ,Biology ,medicine.disease ,Polymorphism, Single Nucleotide ,Proinflammatory cytokine ,Rats ,Interferon-gamma ,medicine.anatomical_structure ,Immunology ,medicine ,Animals ,Proto-Oncogene Proteins c-vav - Abstract
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-γ 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.
- Published
- 2016