ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 3017

TYK2 and Systemic Sclerosis Susceptibility: a New Associated Locus in the IL-12 Pathway

Elena Lopez-Isac1, Lara Bossini-Castillo2, Sandra G Guerra3, Shervin Assassi4, Carmen P. Simeón5, Patricia E. Carreira6, Norberto Ortego-Centeno7, Paloma García de la Peña5, Lorenzo Beretta8, Alessandro Santaniello9, Chiara Bellocchi10, Claudio Lunardi11, Gianluca Moroncini12, Armando Gabrielli13, Gabriela Riemekasten14, Torsten Witte15, Nicolas Hunzelmann16, Alexander Kreuter17, Jorg HW. Distler18, Alexandre E. Voskuyl19, J.K. de Vries-Bouwstra20, Ariane L. Herrick21, Jane Worthington22, Christopher P. Denton23, Carmen Fonseca3, T.R.D.J. Radstake24, Maureen D Mayes25 and Javier Martín1, 1Institute of Parasitology and Biomedicine López-Neyra, IPBLN-CSIC, Granada, Spain, 2Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, PTS Granada, Granada, Spain, 3Centre for Rheumatology, Royal Free and University College Medical School, London, United Kingdom, 4Rheumatology, University of Texas Medical School at Houston, Houston, TX, 5Rheumatologist, Granada, Spain, 6Rheumatology, Hospital Universitario 12 de Octubre, Madrid, Spain, 7Systemic Autoimmune Diseases Unit, Hospital Universitario San Cecilio, Granada, Spain, 8Rheumatology, Milan, Italy, 9Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena and University of Milan, Italy, Milan, Italy, 10Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy, 11Department of Medicine, Università degli Studi di Verona, Verona, Italy, 12Dipartimento di Scienze mediche e Chirurgiche, Università politecnica delle Marche, Ancona, Italy, 13Clinica Medica, Università Politecnica delle Marche, Ancona, Italy, 14Clinic of Rheumatology and Clinical Immunology, Berlin, Germany, 15Department of Immunology and Rheumatology, Hannover Medical School, Hannover, Germany, 16Department of Dermatology, University of Cologne, Cologne, Germany, 17Department of Dermatology, Venereology, and Allergologie, HELIOS St. Elisabeth Hospital, Oberhausen, Germany, 18Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, 19Rheumatology, Amsterdam Rheumatology and immunology Center, location VU University medical center, Amsterdam, Netherlands, 20Rheumatology, Leiden University Medical Center, Leiden, Netherlands, 21Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom, 22Arthritis Research UK Epidemiology Unit, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United Kingdom, 23Rheumatology and Connective Tissue Diseases, University College London, London, United Kingdom, 24Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, Netherlands, 25University of Texas - Houston Medical School, Houston, TX

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: ,

Session Information

Date: Tuesday, November 10, 2015

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics Poster II

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Systemic sclerosis (SSc) is a complex autoimmune disease. The aetiology of the disease is largely unknown, although both environmental and a genetic factors are thought to be involved in the disease development. The genetic susceptibility of SSc has been well-addressed by powered genetic association studies. The results of these studies clearly support an important role of the immune system. In this regard, several interleukin-12 (IL-12) pathway-related genes have been identified as susceptibility factors for SSc (IL12RB1, IL12RB2, IL12A, STAT4). TYK2 is a tyrosine kinase protein that mediates several family cytokines signaling, including IL-12, and constitutes a common risk factor for autoimmunity. On this base, we aimed to analyze the association of the TYK2 locus with SSc susceptibility.      

Methods: The complete set of individuals enrolled for this study comprised a total of 7,103 SSc patients and 12,220 healthy controls of Caucasian ancestry from Spain, USA, Germany, The Netherlands, Italy and the United Kingdom. We performed an initial screening of TYK2 genetic region in a previously published large-scale genetic study (Immunochip). Four TYK2single-nucleotide polymorphisms (SNPs) were selected for follow-up (V362F [rs2304256], P1104A [rs34536443], I684S [rs12720356] and A928V [rs35018800]). 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 clearly supported that the highly significant association observed for V362F with SSc was a spurious signal driven by P1104A, A928V and I684S. This results are consistent with previous in vitro and in silicostudies, which revealed that P1104A, A928V, and I684S were damaging mutations and impaired the catalytic activity of TYK2, leading to a reduced TYK2 response and decreasing pro-inflammatory cytokines signaling, such as IL-12. 

Conclusion:

The present study reports for the first time robust evidence for the implication of TYK2 in SSc susceptibility. These results reinforce the crucial involvement of IL-12 signaling axis in the disease pathophysiology. Thus, target therapies blocking this pathway might represent an effective treatment for the disease.

Disclosure: E. Lopez-Isac, None; L. Bossini-Castillo, None; S. G. Guerra, None; S. Assassi, None; C. P. Simeón, None; P. E. Carreira, None; N. Ortego-Centeno, None; P. García de la Peña, None; L. Beretta, None; A. Santaniello, None; C. Bellocchi, None; C. Lunardi, None; G. Moroncini, None; A. Gabrielli, None; G. Riemekasten, None; T. Witte, None; N. Hunzelmann, None; A. Kreuter, None; J. H. Distler, None; A. E. Voskuyl, None; J. K. de Vries-Bouwstra, None; A. L. Herrick, None; J. Worthington, None; C. P. Denton, GlaxoSmithKline, 2,Actelion Pharmaceuticals US, 5,GlaxoSmithKline, 5,Serono, 5,Inventiva, 5,CSL Behring, 2,Bayer, 5; C. Fonseca, None; T. R. D. J. Radstake, None; M. D. Mayes, None; J. Martín, None.

To cite this abstract in AMA style:

Lopez-Isac E, Bossini-Castillo L, Guerra SG, Assassi S, Simeón CP, Carreira PE, Ortego-Centeno N, García de la Peña P, Beretta L, Santaniello A, Bellocchi C, Lunardi C, Moroncini G, Gabrielli A, Riemekasten G, Witte T, Hunzelmann N, Kreuter A, Distler JH, Voskuyl AE, de Vries-Bouwstra JK, Herrick AL, Worthington J, Denton CP, Fonseca C, Radstake TRDJ, Mayes MD, Martín J. TYK2 and Systemic Sclerosis Susceptibility: a New Associated Locus in the IL-12 Pathway [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/tyk2-and-systemic-sclerosis-susceptibility-a-new-associated-locus-in-the-il-12-pathway/. Accessed .

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