Influence of TYK2 in systemic sclerosis susceptibility: a new locus in the IL-12 pathway.
Lopez-Isac, Elena; Campillo-Davo, Diana; Bossini-Castillo, Lara; Guerra, Sandra G; Assassi, Shervin; Simeon, Carmen Pilar; Carreira, Patricia; Ortego-Centeno, Norberto; Garcia de la Pena, Paloma; the Spanish Scleroderma Group; Beretta, Lorenzo; Santaniello, Alessandro; Bellocchi, Chiara; Lunardi, Claudio; Moroncini, Gianluca; Gabrielli, Armando; Riemekasten, Gabriela; Witte, Torsten; Hunzelmann, Nicolas; Kreuter, Alexander; Distler, Jorg HW; Voskuyl, Alexandre E; de Vries-Bouwstra, Jeska; Herrick, Ariane; Worthington, Jane; Denton, Christopher P; Fonseca, Carmen; Radstake, Timothy RDJ; Mayes, Maureen D; Martin, Javier; the Spanish Scleroderma Group; Rios, Raquel; Callejas, Jose Luis; Hitos, Jose Antonio Vargas; Portales, Rosa Garcia; Camps, Maria Teresa; Fernandez-Nebro, Antonio; Gonzalez-Escribano, Maria F; Garcia-Hernandez, Francisco Jose; Castillo, M Jesus; Aguirre, M Angeles; Gomez-Gracia, Inmaculada; Fernandez-Gutierrez, Benjamin; Rodriguez-Rodriguez, Luis; Vicente, Esther; Andreu, Jose Luis; de Castro, Monica Fernandez; Lopez-Longo, Francisco Javier; Martinez, Lina; Fonollosa, Vicente; Guillen, Alfredo; Castellvi, Ivan; Espinosa, Gerard; Tolosa, Carlos; Pros, Anna; Carballeira, Monica Rodriguez; Narvaez, Francisco Javier; Rivas, Manel Rubio; Santamaria, Vera Ortiz; Madronero, Ana Belen; Gonzalez-Gay, Miguel Angel; Diaz, Bernardino; Trapiella, Luis; Freire, Mayka; Sousa, Adrian; Egurbide, Maria Victoria; Mateo, Patricia Fanlo; Saez-Comet, Luis; Diaz, Federico; Hernandez, Vanesa; Beltran, Emma; Roman-Ivorra, Jose Andres; Grau, Elena; Sancho, Juan Jose Alegre; Garcia, Francisco J. Blanco; Oreiro, Natividad
[Report]
Annals of the Rheumatic Diseases.
75(8):1521-1526, August 2016.
(Format: HTML, PDF)
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=3.08x10-13, OR=0.83), while the association of P1104A, A928V and I684S rare and low-frequency missense variants remained significant with nominal signals (p=2.28x10-3, OR=0.80; p=1.27x10-3, OR=0.59; p=2.63x10-5, 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.
(C) 2016 BMJ Publishing Group Ltd and European League Against Rheumatism
