Influence of TYK2 in systemic sclerosis susceptibility: a new locus in the IL-12 pathway.

Elena López-Isac, Diana Campillo-Davo, Lara Bossini-Castillo, Sandra G Guerra, Shervin Assassi, Carmen Pilar Simeón, Patricia Carreira, Norberto Ortego-Centeno, Paloma García de la Peña, Lorenzo Beretta, Alessandro Santaniello, Chiara Bellocchi, Claudio Lunardi, Gianluca Moroncini, Armando Gabrielli, Gabriela Riemekasten, Torsten Witte, Nicolas Hunzelmann, Alexander Kreuter, Jörg Hw DistlerAlexandre E Voskuyl, Jeska de Vries-Bouwstra, Ariane Herrick, Jane Worthington, Christopher P Denton, Carmen Fonseca, Timothy Rdj Radstake, Maureen D Mayes, Javier Martín, Raquel Ríos (Collaborator), Jose Luis Callejas (Collaborator), José Antonio Vargas Hitos (Collaborator), Rosa García Portales (Collaborator), María Teresa Camps (Collaborator), Antonio Fernández-Nebro (Collaborator), María F González-Escribano (Collaborator), Francisco José García-Hernández (Collaborator), M Jesús Castillo (Collaborator), M Ángeles Aguirre (Collaborator), Inmaculada Gómez-Gracia (Collaborator), Benjamín Fernández-Gutiérrez (Collaborator), Luis Rodríguez-Rodríguez (Collaborator), Esther Vicente (Collaborator), José Luis Andreu (Collaborator), Mónica Fernández de Castro (Collaborator), Francisco Javier López-Longo (Collaborator), Lina Martínez (Collaborator), Vicente Fonollosa (Collaborator), Alfredo Guillén (Collaborator), Iván Castellví (Collaborator), Gerard Espinosa (Collaborator), Carlos Tolosa (Collaborator), Anna Pros (Collaborator), Mónica Rodríguez Carballeira (Collaborator), Francisco Javier Narváez (Collaborator), Manel Rubio Rivas (Collaborator), Vera Ortiz Santamaría (Collaborator), Ana Belén Madroñero (Collaborator), Miguel Ángel González-Gay (Collaborator), Bernardino Díaz (Collaborator), Luis Trapiella (Collaborator), Mayka Freire (Collaborator), Adrián Sousa (Collaborator), María Victoria Egurbide (Collaborator), Patricia Fanlo Mateo (Collaborator), Luis Sáez-Comet (Collaborator), Federico Díaz (Collaborator), Vanesa Hernández (Collaborator), Emma Beltrán (Collaborator), José Andrés Román-Ivorra (Collaborator), Elena Grau (Collaborator), Juan José Alegre Sancho (Collaborator), Francisco J Blanco García (Collaborator), Natividad Oreiro (Collaborator)

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)1521-1526
JournalAnnals of the rheumatic diseases
Issue number8
Early online date2 Sept 2015
Publication statusPublished - Aug 2016


  • Cytokines
  • Gene Polymorphism
  • Systemic Sclerosis
  • Treatment


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