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

Spanish Scleroderma Group, 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 KreuterJörg Hw Distler, Alexandre E Voskuyl, Jeska de Vries-Bouwstra, Ariane Herrick, Jane Worthington, Christopher P Denton, Carmen Fonseca, Timothy Rdj Radstake, Maureen D Mayes, Javier Martín

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.
OriginalspracheEnglisch
ZeitschriftAnnals of the Rheumatic Diseases
Jahrgang75
Ausgabenummer8
Seiten (von - bis)1521-6
Seitenumfang6
ISSN0003-4967
DOIs
PublikationsstatusVeröffentlicht - 08.2016

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