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

Lopez-Isac E, Campillo-Davo D, Bossini-Castillo L, Guerra SG, Assassi S, Pilar Simeon C, Carreira P, Ortego-Centeno N, Garcia De La Pena P, Beretta L, Santaniello A, Bellocchi C, Lunardi C, Moroncini G, Gabrielli A, Riemekasten G, Witte T, Hunzelmann N, Kreuter A, Distler J, Voskuyl AE, De Vries-Bouwstra J, Herrick A, Worthington J, Denton CP, Fonseca C, Radstake TRDJ, Mayes MD, Martin J (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Book Volume: 75

Pages Range: 1521-6

Journal Issue: 8

DOI: 10.1136/annrheumdis-2015-208154

Abstract

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

Authors with CRIS profile

Involved external institutions

Spanish National Research Council / Consejo Superior de Investigaciones Científicas (CSIC) Spain (ES) Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico Italy (IT) University Medical Centre Utrecht (UMC Utrecht) Netherlands (NL) University of Manchester United Kingdom (GB) University College London (UCL) United Kingdom (GB) University of Texas Health Science Center at Houston (UTHealth) United States (USA) (US) Vall d'Hebron University Hospital / Hospital Universitari Vall d'Hebron Spain (ES) Hospital Universitario 12 de Octubre Spain (ES) Università Politecnica delle Marche (UNIVPM) / Marche Polytechnic University Italy (IT) Vrije Universiteit Amsterdam (VU) / University Amsterdam Netherlands (NL) Universidad de Granada Spain (ES) University of Verona / Università degli Studi di Verona Italy (IT) Charité - Universitätsmedizin Berlin Germany (DE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Universität zu Köln Germany (DE) HELIOS Kliniken Germany (DE) Leiden University Netherlands (NL)

How to cite

APA:

Lopez-Isac, E., Campillo-Davo, D., Bossini-Castillo, L., Guerra, S.G., Assassi, S., Pilar Simeon, C.,... Martin, J. (2016). Influence of TYK2 in systemic sclerosis susceptibility: a new locus in the IL-12 pathway. Annals of the Rheumatic Diseases, 75(8), 1521-6. https://doi.org/10.1136/annrheumdis-2015-208154

MLA:

Lopez-Isac, Elena, et al. "Influence of TYK2 in systemic sclerosis susceptibility: a new locus in the IL-12 pathway." Annals of the Rheumatic Diseases 75.8 (2016): 1521-6.

BibTeX: Download