TY - JOUR
T1 - Influence of TYK2 in systemic sclerosis susceptibility
T2 - 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
N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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.
U2 - 10.1136/annrheumdis-2015-208154
DO - 10.1136/annrheumdis-2015-208154
M3 - Article
C2 - 26338038
SN - 0003-4967
VL - 75
SP - 1521
EP - 1526
JO - Annals of the Rheumatic Diseases
JF - Annals of the Rheumatic Diseases
IS - 8
ER -