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

Genes & Immunity volume 18, pages 48–56 (2017)Cite this article

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A Corrigendum to this article was published on 27 April 2017

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.

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Acknowledgements

This work was supported by grants from the Knut and Alice Wallenberg Foundation, the Borje Dahlin Foundation, the Swedish Association against Rheumatism (Svenska Reumatikerförbundet), the Swedish Medical Research Council (Vetenskapsrådet), the Swedish Innovation Agency (Combine - Vinnova), the Swedish Foundation for Strategic Research (SSF), the European Community’s Seventh Framework Program (FP7/2007-2013) under the grant agreement N° HEALTH-F4-2010-241504 (EURATRANS), as well as the IMI project BeTheCURE.

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Authors and Affiliations

  1. Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden

    A O Guerreiro-Cacais, A Gyllenberg, R Berglund, A D Beyeen, M Jagodic, T Olsson & I Kockum

  2. Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

    U Norin & R Holmdahl

  3. GenHotel-EA3886, Evry-Val d’Essonne University, Evry-Genopole, France

    E Petit-Teixeira

  4. GenHotel-Auvergne, CHU de Clermont-Ferrand, Auvergne University, France

    F Cornélis

  5. Inserm, U1043, Toulouse, France

    A Saoudi & G J Fournié

  6. CNRS, U5282, Toulouse, France

    A Saoudi & G J Fournié

  7. Centre de Physiopathologie de Toulouse Purpan, Université de Toulouse, Toulouse, France

    A Saoudi & G J Fournié

  8. Department of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

    L Alfredsson

  9. Department of Medicine, Rheumatology Unit, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden

    L Klareskog & L Padyukov

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Correspondence to A O Guerreiro-Cacais.

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Guerreiro-Cacais, A., Norin, U., Gyllenberg, A. et al. VAV1 regulates experimental autoimmune arthritis and is associated with anti-CCP negative rheumatoid arthritis. Genes Immun 18, 48–56 (2017). https://doi.org/10.1038/gene.2016.49

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