Influence of TYK2 in systemic sclerosis susceptibility: a new locus in the IL-12 pathway.
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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, García de la Peña Paloma, Spanish Scleroderma Group, 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, Martín Javier
Аннотация
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.