VAV1 regulates experimental autoimmune arthritis and is associated with anti-CCP negative rheumatoid arthritis

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Guerreiro-Cacais, A | Norin, U | Gyllenberg, A | Berglund, R | Beyeen, A | Petit-Teixeira, E | Cornélis, F | Saoudi, A | Fournié, G | Holmdahl, R | Alfredsson, L | Klareskog, L | Jagodic, M | Olsson, T | Kockum, I | Padyukov, L

Edité par CCSD ; Nature Publishing Group: Open Access Hybrid Model Option B -

International audience. 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.

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