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- DOI: 10.1136/annrheumdis-2015-208154
- PMID: 26338038
- UKPMCID: 26338038
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Influence of TYK2 in systemic sclerosis susceptibility: a new locus in the IL-12 pathway.
López-Isac, Elena; Campillo-Davo, Diana; Bossini-Castillo, Lara; Guerra, Sandra G; Assassi, Shervin; Simeón, Carmen Pilar; Carreira, Patricia; Ortego-Centeno, Norberto; GarcÃa de la Peña, Paloma; Beretta, Lorenzo; Santaniello, Alessandro; Bellocchi, Chiara; Lunardi, Claudio; Moroncini, Gianluca; Gabrielli, Armando; Riemekasten, Gabriela; Witte, Torsten; Hunzelmann, Nicolas; Kreuter, Alexander; Distler, Jörg Hw; Voskuyl, Alexandre E; de Vries-Bouwstra, Jeska; Herrick, Ariane; Worthington, Jane; Denton, Christopher P; Fonseca, Carmen; Radstake, Timothy Rdj; Mayes, Maureen D; MartÃn, Javier
Annals of the rheumatic diseases. 2015;.
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Full-text held externally
- DOI: 10.1136/annrheumdis-2015-208154
- PMID: 26338038
- UKPMCID: 26338038
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.
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- López-Isac, Elena
- Campillo-Davo, Diana
- Bossini-Castillo, Lara
- Guerra, Sandra G
- Assassi, Shervin
- Simeón, Carmen Pilar
- Carreira, Patricia
- Ortego-Centeno, Norberto
- GarcÃa de la Peña, Paloma
- Beretta, Lorenzo
- Santaniello, Alessandro
- Bellocchi, Chiara
- Lunardi, Claudio
- Moroncini, Gianluca
- Gabrielli, Armando
- Riemekasten, Gabriela
- Witte, Torsten
- Hunzelmann, Nicolas
- Kreuter, Alexander
- Distler, Jörg Hw
- Voskuyl, Alexandre E
- de Vries-Bouwstra, Jeska
- Herrick, Ariane
- Worthington, Jane
- Denton, Christopher P
- Fonseca, Carmen
- Radstake, Timothy Rdj
- Mayes, Maureen D
- MartÃn, Javier
- RÃos, Raquel
- Callejas, Jose Luis
- Hitos, José Antonio Vargas
- Portales, Rosa GarcÃa
- Camps, MarÃa Teresa
- Fernández-Nebro, Antonio
- González-Escribano, MarÃa F
- GarcÃa-Hernández, Francisco José
- Castillo, M Jesús
- Aguirre, M Ãngeles
- Gómez-Gracia, Inmaculada
- Fernández-Gutiérrez, BenjamÃn
- RodrÃguez-RodrÃguez, Luis
- Vicente, Esther
- Andreu, José Luis
- de Castro, Mónica Fernández
- López-Longo, Francisco Javier
- MartÃnez, Lina
- Fonollosa, Vicente
- Guillén, Alfredo
- CastellvÃ, Iván
- Espinosa, Gerard
- Tolosa, Carlos
- Pros, Anna
- Carballeira, Mónica RodrÃguez
- Narváez, Francisco Javier
- Rivas, Manel Rubio
- SantamarÃa, Vera Ortiz
- Madroñero, Ana Belén
- González-Gay, Miguel Ãngel
- DÃaz, Bernardino
- Trapiella, Luis
- Freire, Mayka
- Sousa, Adrián
- Egurbide, MarÃa Victoria
- Mateo, Patricia Fanlo
- Sáez-Comet, Luis
- DÃaz, Federico
- Hernández, Vanesa
- Beltrán, Emma
- Román-Ivorra, José Andrés
- Grau, Elena
- Sancho, Juan José Alegre
- GarcÃa, Francisco J Blanco
- Oreiro, Natividad