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

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.

Otras publicaciones de la misma revista o congreso con autores/as de la Universidad de Cantabria

 Fuente: Annals of the Rheumatic Diseases, 2016, 75(8), 1521-1526

Editorial: BMJ Publishing Group

 Año de publicación: 2016

Nº de páginas: 7

Tipo de publicación: Artículo de Revista

 DOI: 10.1136/annrheumdis-2015-208154

ISSN: 0003-4967,1468-2060

 Proyecto español: SAF2009-11110 ; SAF2012-34435

Autoría

LÓPEZ ISAC, ELENA

CAMPILLO DAVO, DIANA

BOSSINI CASTILLO, LARA

GUERRA, SANDRA G.

ASSASSI, SHERVIN

SIMEÓN, CARMEN PILAR

CARREIRA, PATRICIA

ORTEGO CENTENO, NORBERTO

GARCÍA DE LA PEÑA, PALOMA

BERETTA, LORENZO

SANTANIELLO, ALESSANDRO

BELLOCCHI, CHIARA

LUNARDI, CLAUDIO

MORONCINI, GIANLUCA

GABRIELLI, ARMANDO

RIEMEKASTEN, GABRIELA

WITTE, TORSTEN

HUNZELMANN, NICOLAS

KREUTER, ALEXANDER