Lopez-Isac, Elena ORCID: 0000-0001-8806-5148, Campillo-Davo, Diana ORCID: 0000-0002-6080-3935, Bossini-Castillo, Lara ORCID: 0000-0002-5471-5824, Guerra, Sandra G., Assassi, Shervin, Pilar Simeon, Carmen, Carreira, Patricia, Ortego-Centeno, Norberto, Garcia de la Pena, Paloma, Beretta, Lorenzo ORCID: 0000-0002-6529-6258, Santaniello, Alessandro, Bellocchi, Chiara, Lunardi, Claudio, Moroncini, Gianluca, Gabrielli, Armando, Riemekasten, Gabriela, Witte, Torsten, Hunzelmann, Nicolas, Kreuter, Alexander, Distler, Jorg H. W., Voskuyl, Alexandre E., de Vries-Bouwstra, Jeska, Herrick, Ariane, Worthington, Jane, Denton, Christopher P., Fonseca, Carmen, Radstake, Timothy R. D. J., Mayes, Maureen D. and Martin, Javier ORCID: 0000-0002-2202-0622 (2016). Influence of TYK2 in systemic sclerosis susceptibility: a new locus in the IL-12 pathway. Ann. Rheum. Dis., 75 (8). S. 1521 - 1527. LONDON: BMJ PUBLISHING GROUP. ISSN 1468-2060

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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=3.08x10(-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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Lopez-Isac, ElenaUNSPECIFIEDorcid.org/0000-0001-8806-5148UNSPECIFIED
Campillo-Davo, DianaUNSPECIFIEDorcid.org/0000-0002-6080-3935UNSPECIFIED
Bossini-Castillo, LaraUNSPECIFIEDorcid.org/0000-0002-5471-5824UNSPECIFIED
Guerra, Sandra G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Assassi, ShervinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pilar Simeon, CarmenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carreira, PatriciaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ortego-Centeno, NorbertoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garcia de la Pena, PalomaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beretta, LorenzoUNSPECIFIEDorcid.org/0000-0002-6529-6258UNSPECIFIED
Santaniello, AlessandroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bellocchi, ChiaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lunardi, ClaudioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moroncini, GianlucaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gabrielli, ArmandoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riemekasten, GabrielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Witte, TorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hunzelmann, NicolasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kreuter, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Distler, Jorg H. W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Voskuyl, Alexandre E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Vries-Bouwstra, JeskaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herrick, ArianeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Worthington, JaneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Denton, Christopher P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fonseca, CarmenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Radstake, Timothy R. D. J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mayes, Maureen D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martin, JavierUNSPECIFIEDorcid.org/0000-0002-2202-0622UNSPECIFIED
URN: urn:nbn:de:hbz:38-268468
DOI: 10.1136/annrheumdis-2015-208154
Journal or Publication Title: Ann. Rheum. Dis.
Volume: 75
Number: 8
Page Range: S. 1521 - 1527
Date: 2016
Publisher: BMJ PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1468-2060
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENOME-WIDE ASSOCIATION; INTERLEUKIN-12/23 MONOCLONAL-ANTIBODY; TYROSINE KINASE 2; RHEUMATOID-ARTHRITIS; LUPUS-ERYTHEMATOSUS; DOUBLE-BLIND; DISEASE; IDENTIFICATION; PSORIASIS; USTEKINUMABMultiple languages
RheumatologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/26846

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