RT Journal Article
T1 Influence of TYK2 in systemic sclerosis susceptibility: a new locus in the IL-12 pathway.
A1 López-Isac, Elena
A1 Campillo-Davo, Diana
A1 Bossini-Castillo, Lara
A1 Guerra, Sandra G
A1 Assassi, Shervin
A1 Simeón, Carmen Pilar
A1 Carreira, Patricia
A1 Ortego-Centeno, Norberto
A1 García de la Peña, Paloma
A1 Spanish Scleroderma Group, 
A1 Beretta, Lorenzo
A1 Santaniello, Alessandro
A1 Bellocchi, Chiara
A1 Lunardi, Claudio
A1 Moroncini, Gianluca
A1 Gabrielli, Armando
A1 Riemekasten, Gabriela
A1 Witte, Torsten
A1 Hunzelmann, Nicolas
A1 Kreuter, Alexander
A1 Distler, Jörg Hw
A1 Voskuyl, Alexandre E
A1 de Vries-Bouwstra, Jeska
A1 Herrick, Ariane
A1 Worthington, Jane
A1 Denton, Christopher P
A1 Fonseca, Carmen
A1 Radstake, Timothy Rdj
A1 Mayes, Maureen D
A1 Martín, Javier
K1 Cytokines
K1 Gene Polymorphism
K1 Systemic Sclerosis
K1 Treatment
AB 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. 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. 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. We report for the first time the association of TYK2 with SSc and reinforce the relevance of the IL-12 pathway in SSc pathophysiology.
YR 2015
FD 2015-09-02
LK http://hdl.handle.net/10668/10172
UL http://hdl.handle.net/10668/10172
LA en
DS RISalud
RD Apr 18, 2025