Influence of TYK2 in systemic sclerosis susceptibility: a new locus in the IL-12 pathway.
OBJECTIVE
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.
Institute of Parasitology and Biomedicine López-Neyra, IPBLN-CSIC, PTS Granada, Granada, Spain.
Elena
E
López-Isac
Institute of Parasitology and Biomedicine López-Neyra, IPBLN-CSIC, PTS Granada, Granada, Spain.
Diana
D
Campillo-Davo
Institute of Parasitology and Biomedicine López-Neyra, IPBLN-CSIC, PTS Granada, Granada, Spain.
Lara
L
Bossini-Castillo
Centre for Rheumatology, Royal Free and University College Medical School, London, UK.
Sandra G
SG
Guerra
Division of Rheumatology and Clinical Immunogenetics, The University of Texas Health Science Center-Houston, Houston, USA.
Shervin
S
Assassi
Department of Internal Medicine, Valle de Hebrón Hospital, Barcelona, Spain.
Carmen Pilar
CP
Simeón
Department of Rheumatology, 12 de Octubre University Hospital, Madrid, Spain.
Patricia
P
Carreira
Department of Internal Medicine, Clinic University Hospital, Granada, Spain.
Norberto
N
Ortego-Centeno
Department of Rheumatology, Madrid Norte Sanchinarro Hospital, Madrid, Spain.
Paloma
P
García de la Peña
Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy.
Lorenzo
L
Beretta
Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy.
Alessandro
A
Santaniello
Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy.
Chiara
C
Bellocchi
Department of Medicine, Università degli Studi di Verona, Verona, Italy.
Claudio
C
Lunardi
Clinica Medica, Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche and Ospedali Riuniti, Ancona, Italy.
Gianluca
G
Moroncini
Clinica Medica, Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche and Ospedali Riuniti, Ancona, Italy.
Armando
A
Gabrielli
Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany.
Gabriela
G
Riemekasten
Department of Clinical Immunology, Hannover Medical School, Hannover, Germany.
Torsten
T
Witte
Department of Dermatology, University of Cologne, Cologne, Germany.
Nicolas
N
Hunzelmann
Department of Dermatology, Venereology, and Allergology, HELIOS St Elisabeth Hospital Oberhausen, Germany.
Alexander
A
Kreuter
Department of Internal Medicine, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
Jörg Hw
JH
Distler
Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands.
Alexandre E
AE
Voskuyl
Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
Jeska
J
de Vries-Bouwstra
Centre for Musculoskeletal Research and NIHR Manchester Musculoskeletal Biomedical Research Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
Ariane
A
Herrick
Centre for Musculoskeletal Research and NIHR Manchester Musculoskeletal Biomedical Research Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
Jane
J
Worthington
Centre for Rheumatology, Royal Free and University College Medical School, London, UK.
Christopher P
CP
Denton
Centre for Rheumatology, Royal Free and University College Medical School, London, UK.
Carmen
C
Fonseca
Department of Rheumatology & Clinical Immunology, Laboratory of Translational Immunology, department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
Timothy Rdj
TR
Radstake
Division of Rheumatology and Clinical Immunogenetics, The University of Texas Health Science Center-Houston, Houston, USA.
Maureen D
MD
Mayes
Institute of Parasitology and Biomedicine López-Neyra, IPBLN-CSIC, PTS Granada, Granada, Spain.
Javier
J
Martín
D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D018664:Interleukin-12 / Q000502:physiology*; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D053634:TYK2 Kinase / Q000235:genetics*
D018664:Interleukin-12; D053634:TYK2 Kinase; C070139:TYK2 protein, human
Cytokines; Gene Polymorphism; Systemic Sclerosis; Treatment