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Influence of TYK2 in systemic sclerosis susceptibility: a new locus in the IL-12 pathway
  1. Elena López-Isac1,
  2. Diana Campillo-Davo1,
  3. Lara Bossini-Castillo1,
  4. Sandra G Guerra2,
  5. Shervin Assassi3,
  6. Carmen Pilar Simeón4,
  7. Patricia Carreira5,
  8. Norberto Ortego-Centeno6,
  9. Paloma García de la Peña7,
  10. the Spanish Scleroderma Group,
  11. Lorenzo Beretta8,
  12. Alessandro Santaniello8,
  13. Chiara Bellocchi8,
  14. Claudio Lunardi9,
  15. Gianluca Moroncini10,
  16. Armando Gabrielli10,
  17. Gabriela Riemekasten11,12,
  18. Torsten Witte13,
  19. Nicolas Hunzelmann14,
  20. Alexander Kreuter15,
  21. Jörg HW Distler16,
  22. Alexandre E Voskuyl17,
  23. Jeska de Vries-Bouwstra18,
  24. Ariane Herrick19,
  25. Jane Worthington19,
  26. Christopher P Denton2,
  27. Carmen Fonseca2,
  28. Timothy RDJ Radstake20,
  29. Maureen D Mayes3,
  30. Javier Martín1
    1. 1Institute of Parasitology and Biomedicine López-Neyra, IPBLN-CSIC, PTS Granada, Granada, Spain
    2. 2Centre for Rheumatology, Royal Free and University College Medical School, London, UK
    3. 3Division of Rheumatology and Clinical Immunogenetics, The University of Texas Health Science Center–Houston, Houston, USA
    4. 4Department of Internal Medicine, Valle de Hebrón Hospital, Barcelona, Spain
    5. 5Department of Rheumatology, 12 de Octubre University Hospital, Madrid, Spain
    6. 6Department of Internal Medicine, Clinic University Hospital, Granada, Spain
    7. 7Department of Rheumatology, Madrid Norte Sanchinarro Hospital, Madrid, Spain
    8. 8Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy
    9. 9Department of Medicine, Università degli Studi di Verona, Verona, Italy
    10. 10Clinica Medica, Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche and Ospedali Riuniti, Ancona, Italy
    11. 11Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany
    12. 12German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany
    13. 13Department of Clinical Immunology, Hannover Medical School, Hannover, Germany
    14. 14Department of Dermatology, University of Cologne, Cologne, Germany
    15. 15Department of Dermatology, Venereology, and Allergology, HELIOS St Elisabeth Hospital Oberhausen, Germany
    16. 16Department of Internal Medicine, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
    17. 17Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands
    18. 18Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
    19. 19Centre for Musculoskeletal Research and NIHR Manchester Musculoskeletal Biomedical Research Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
    20. 20Department of Rheumatology & Clinical Immunology, Laboratory of Translational Immunology, department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
    1. Correspondence to Dr Javier Martin, Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC. Parque Tecnológico Ciencias de la Salud. Avenida del Conocimiento s/n Armilla (Granada) 18016, Spain; martin{at}


    Objectives TYK2 is a common genetic risk factor for several autoimmune diseases. This gene encodes a protein kinase involved in interleukin 12 (IL-12) pathway, which is a well-known player in the pathogenesis of systemic sclerosis (SSc). Therefore, we aimed to assess the possible role of this locus in SSc.

    Methods This study comprised a total of 7103 patients with SSc and 12 220 healthy controls of European ancestry from Spain, USA, Germany, the Netherlands, Italy and the UK. Four TYK2 single-nucleotide polymorphisms (V362F (rs2304256), P1104A (rs34536443), I684S (rs12720356) and A928V (rs35018800)) were selected for follow-up based on the results of an Immunochip screening phase of the locus. Association and dependence analyses were performed by the means of logistic regression and conditional logistic regression. Meta-analyses were performed using the inverse variance method.

    Results Genome-wide significance level was reached for TYK2 V362F common variant in our pooled analysis (p=3.08×10−13, OR=0.83), while the association of P1104A, A928V and I684S rare and low-frequency missense variants remained significant with nominal signals (p=2.28×10−3, OR=0.80; p=1.27×10−3, OR=0.59; p=2.63×10−5, OR=0.83, respectively). Interestingly, dependence and allelic combination analyses showed that the strong association observed for V362F with SSc, corresponded to a synthetic association dependent on the effect of the three previously mentioned TYK2 missense variants.

    Conclusions We report for the first time the association of TYK2 with SSc and reinforce the relevance of the IL-12 pathway in SSc pathophysiology.

    • Systemic Sclerosis
    • Gene Polymorphism
    • Cytokines
    • Treatment

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