TY - JOUR
T1 - Influence of TYK2 in systemic sclerosis susceptibility: a new locus in the IL-12 pathway.
AU - López-Isac, Elena
AU - Campillo-Davo, Diana
AU - Bossini-Castillo, Lara
AU - Guerra, Sandra G
AU - Assassi, Shervin
AU - Simeón, Carmen Pilar
AU - Carreira, Patricia
AU - Ortego-Centeno, Norberto
AU - García de la Peña, Paloma
AU - Beretta, Lorenzo
AU - Santaniello, Alessandro
AU - Bellocchi, Chiara
AU - Lunardi, Claudio
AU - Moroncini, Gianluca
AU - Gabrielli, Armando
AU - Riemekasten, Gabriela
AU - Witte, Torsten
AU - Hunzelmann, Nicolas
AU - Kreuter, Alexander
AU - Distler, Jörg Hw
AU - Voskuyl, Alexandre E
AU - de Vries-Bouwstra, Jeska
AU - Herrick, Ariane
AU - Worthington, Jane
AU - Denton, Christopher P
AU - Fonseca, Carmen
AU - Radstake, Timothy Rdj
AU - Mayes, Maureen D
AU - Martín, Javier
A2 - Ríos, Raquel
A2 - Callejas, Jose Luis
A2 - Hitos, José Antonio Vargas
A2 - Portales, Rosa García
A2 - Camps, María Teresa
A2 - Fernández-Nebro, Antonio
A2 - González-Escribano, María F
A2 - García-Hernández, Francisco José
A2 - Castillo, M Jesús
A2 - Aguirre, M Ángeles
A2 - Gómez-Gracia, Inmaculada
A2 - Fernández-Gutiérrez, Benjamín
A2 - Rodríguez-Rodríguez, Luis
A2 - Vicente, Esther
A2 - Andreu, José Luis
A2 - de Castro, Mónica Fernández
A2 - López-Longo, Francisco Javier
A2 - Martínez, Lina
A2 - Fonollosa, Vicente
A2 - Guillén, Alfredo
A2 - Castellví, Iván
A2 - Espinosa, Gerard
A2 - Tolosa, Carlos
A2 - Pros, Anna
A2 - Carballeira, Mónica Rodríguez
A2 - Narváez, Francisco Javier
A2 - Rivas, Manel Rubio
A2 - Santamaría, Vera Ortiz
A2 - Madroñero, Ana Belén
A2 - González-Gay, Miguel Ángel
A2 - Díaz, Bernardino
A2 - Trapiella, Luis
A2 - Freire, Mayka
A2 - Sousa, Adrián
A2 - Egurbide, María Victoria
A2 - Mateo, Patricia Fanlo
A2 - Sáez-Comet, Luis
A2 - Díaz, Federico
A2 - Hernández, Vanesa
A2 - Beltrán, Emma
A2 - Román-Ivorra, José Andrés
A2 - Grau, Elena
A2 - Sancho, Juan José Alegre
A2 - García, Francisco J Blanco
A2 - Oreiro, Natividad
PY - 2016/8
Y1 - 2016/8
N2 - 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.
AB - 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.
KW - Cytokines
KW - Gene Polymorphism
KW - Systemic Sclerosis
KW - Treatment
U2 - 10.1136/annrheumdis-2015-208154
DO - 10.1136/annrheumdis-2015-208154
M3 - Article
C2 - 26338038
SN - 1468-2060
VL - 75
SP - 1521
EP - 1526
JO - Annals of the rheumatic diseases
JF - Annals of the rheumatic diseases
IS - 8
ER -