Format

Send to

Choose Destination
Ann Rheum Dis. 2016 Aug;75(8):1521-6. doi: 10.1136/annrheumdis-2015-208154. Epub 2015 Sep 2.

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

Author information

1
Institute of Parasitology and Biomedicine López-Neyra, IPBLN-CSIC, PTS Granada, Granada, Spain.
2
Centre for Rheumatology, Royal Free and University College Medical School, London, UK.
3
Division of Rheumatology and Clinical Immunogenetics, The University of Texas Health Science Center-Houston, Houston, USA.
4
Department of Internal Medicine, Valle de Hebrón Hospital, Barcelona, Spain.
5
Department of Rheumatology, 12 de Octubre University Hospital, Madrid, Spain.
6
Department of Internal Medicine, Clinic University Hospital, Granada, Spain.
7
Department of Rheumatology, Madrid Norte Sanchinarro Hospital, Madrid, Spain.
8
Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy.
9
Department of Medicine, Università degli Studi di Verona, Verona, Italy.
10
Clinica Medica, Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche and Ospedali Riuniti, Ancona, Italy.
11
Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany.
12
Department of Clinical Immunology, Hannover Medical School, Hannover, Germany.
13
Department of Dermatology, University of Cologne, Cologne, Germany.
14
Department of Dermatology, Venereology, and Allergology, HELIOS St Elisabeth Hospital Oberhausen, Germany.
15
Department of Internal Medicine, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
16
Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands.
17
Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
18
Centre for Musculoskeletal Research and NIHR Manchester Musculoskeletal Biomedical Research Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
19
Department of Rheumatology & Clinical Immunology, Laboratory of Translational Immunology, department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.

Abstract

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.

KEYWORDS:

Cytokines; Gene Polymorphism; Systemic Sclerosis; Treatment

PMID:
26338038
DOI:
10.1136/annrheumdis-2015-208154
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire Icon for Diposit Digital de la Universitat de Barcelona
Loading ...
Support Center