A role for VAV1 in experimental autoimmune encephalomyelitis and multiple sclerosis.
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.
Jagodic
Maja
M
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Colacios
Celine
C
Nohra
Rita
R
Dejean
Anne S
AS
Beyeen
Amennai Daniel
AD
Khademi
Mohsen
M
Casemayou
Audrey
A
Lamouroux
Lucille
L
Duthoit
Christine
C
Papapietro
Olivier
O
Sjöholm
Louise
L
Bernard
Isabelle
I
Lagrange
Dominique
D
Dahlman
Ingrid
I
Lundmark
Frida
F
Oturai
Annette B
AB
Soendergaard
Helle B
HB
Kemppinen
Anu
A
Saarela
Janna
J
Tienari
Pentti J
PJ
Harbo
Hanne F
HF
Spurkland
Anne
A
Ramagopalan
Sreeram V
SV
Sadovnick
Dessa A
DA
Ebers
George C
GC
Seddighzadeh
Maria
M
Klareskog
Lars
L
Alfredsson
Lars
L
Padyukov
Leonid
L
Hillert
Jan
J
Clanet
Michel
M
Edan
Gilles
G
Fontaine
Bertrand
B
Fournié
Gilbert J
GJ
Kockum
Ingrid
I
Saoudi
Abdelhadi
A
Olsson
Tomas
T
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000503:physiopathology*; D007371:Interferon-gamma / Q000235:genetics; D009103:Multiple Sclerosis / Q000276:immunology / Q000503:physiopathology*; D020641:Polymorphism, Single Nucleotide; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000502:physiology*; D040641:Quantitative Trait Loci; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D051567:Proto-Oncogene Proteins c-vav; D014409:Tumor Necrosis Factor-alpha; C496620:Vav1 protein, rat; D007371:Interferon-gamma