title: VAV1 regulates experimental autoimmune arthritis and is associated with anti-CCP negative rheumatoid arthritis.
abstract: Rheumatoid arthritis (RA) patients can be stratified into two subgroups defined by the presence or absence of antibodies against citrullinated circular peptides (anti-CCP) with most of the genetic association found in anti-CCP positive RA. Here we addressed the role of VAV1, previously associated to multiple sclerosis (MS), in the pathogenesis of RA in experimental models and in a genetic association study. Experimental arthritis triggered by pristane or collagen type II was induced in DA rats and in the DA.BN-R25 congenic line that carries a polymorphism in Vav1. Difference in arthritis severity was observed only after immunization with pristane. In a case-control study, 34 SNPs from VAV1 locus were analyzed by Immunochip genotyping in 11475 RA patients (7573 anti-CCP positive and 3902 negative) and 15,870 controls in six cohorts of European Caucasians. A combination of the previous MS-associated haplotype and two additional SNPs was associated with anti-CCP negative RA (alleles G-G-A-A of rs682626-rs2546133-rs2617822-rs12979659, OR=1.13, P=1.27 × 10-5). The same markers also contributed to activity of RA at baseline with the strongest association in the anti-CCP negative group for the rs682626-rs12979659 G-A haplotype (β=-0.283, P=0.0048). Our study suggests a role for VAV1 and T-cell signaling in the pathology of anti-CCP-negative RA.
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: A O
authors.initials: AO
authors.lastname: Guerreiro-Cacais
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: U
authors.initials: U
authors.lastname: Norin
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Gyllenberg
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: R
authors.initials: R
authors.lastname: Berglund
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: A D
authors.initials: AD
authors.lastname: Beyeen
authors.affiliation: GenHotel-EA3886, Evry-Val d'Essonne University, Evry-Genopole, France.
authors.forename: E
authors.initials: E
authors.lastname: Petit-Teixeira
authors.affiliation: GenHotel-Auvergne, CHU de Clermont-Ferrand, Auvergne University, France.
authors.forename: F
authors.initials: F
authors.lastname: Cornélis
authors.affiliation: Inserm, U1043, Toulouse, France.|CNRS, U5282, Toulouse, France.|Centre de Physiopathologie de Toulouse Purpan, Université de Toulouse, Toulouse, France.
authors.forename: A
authors.initials: A
authors.lastname: Saoudi
authors.affiliation: Inserm, U1043, Toulouse, France.|CNRS, U5282, Toulouse, France.|Centre de Physiopathologie de Toulouse Purpan, Université de Toulouse, Toulouse, France.
authors.forename: G J
authors.initials: GJ
authors.lastname: Fournié
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: R
authors.initials: R
authors.lastname: Holmdahl
authors.affiliation: Department of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Alfredsson
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Klareskog
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Jagodic
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Olsson
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: I
authors.initials: I
authors.lastname: Kockum
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Padyukov
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000097:blood / Q000235:genetics* / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000097:blood / Q000235:genetics* / Q000276:immunology; D015415:Biomarkers / Q000032:analysis; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D010456:Peptides, Cyclic / Q000276:immunology*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics*; D051381:Rats; D011914:Rats, Inbred BN
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D010456:Peptides, Cyclic; D051567:Proto-Oncogene Proteins c-vav; C496618:VAV1 protein, human; C487763:cyclic citrullinated peptide