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.
| Original language | English |
|---|---|
| Pages (from-to) | 1521-1526 |
| Number of pages | 6 |
| Journal | Annals of the Rheumatic Diseases |
| Volume | 75 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 2016 |
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ASJC Scopus subject areas
- Rheumatology
- Immunology
- Biochemistry, Genetics and Molecular Biology(all)
- Immunology and Allergy
Cite this
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; de la Peña, Paloma García; Beretta, Lorenzo; Santaniello, Alessandro; Bellocchi, Chiara; Lunardi, Claudio; Moroncini, Gianluca; Gabrielli, Armando; Riemekasten, Gabriela; Witte, Torsten; Hunzelmann, Nicolas; Kreuter, Alexander; Distler, Jörg 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.; Martín, Javier; Ríos, Raquel; Callejas, Jose Luis; Hitos, José Antonio Vargas; Portales, Rosa García; Camps, María Teresa; Fernández-Nebro, Antonio; González-Escribano, María F.; García-Hernández, Francisco José; Castillo, M. Jesús; Aguirre, M. ángeles; Gómez-Gracia, Inmaculada; Fernández-Gutiérrez, Benjamín; Rodríguez-Rodríguez, Luis; Vicente, Esther; Andreu, José Luis; de Castro, Mónica Fernández; López-Longo, Francisco Javier; Martínez, Lina; Fonollosa, Vicente; Guillén, Alfredo; Castellví, Iván; Espinosa, Gerard; Tolosa, Carlos; Pros, Anna; Carballeira, Mónica Rodríguez; Narváez, Francisco Javier; Rivas, Manel Rubio; Santamaría, Vera Ortiz; Madroñero, Ana Belén; González-Gay, Miguel ángel; Díaz, Bernardino; Trapiella, Luis; Freire, Mayka; Sousa, Adrián; Egurbide, María Victoria; Mateo, Patricia Fanlo; Sáez-Comet, Luis; Díaz, Federico; Hernánde, Vanesa; Beltrán, Emma; Román-Ivorra, José Andrés; Grau, Elena; Sancho, Juan José Alegre; García, Francisco J Blanco.
In: Annals of the Rheumatic Diseases, Vol. 75, No. 8, 2016, p. 1521-1526.Research output: Contribution to journal › Article
}
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 - de la Peña, Paloma García
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 H W
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 R D J
AU - Mayes, Maureen D.
AU - Martín, Javier
AU - Ríos, Raquel
AU - Callejas, Jose Luis
AU - Hitos, José Antonio Vargas
AU - Portales, Rosa García
AU - Camps, María Teresa
AU - Fernández-Nebro, Antonio
AU - González-Escribano, María F.
AU - García-Hernández, Francisco José
AU - Castillo, M. Jesús
AU - Aguirre, M. ángeles
AU - Gómez-Gracia, Inmaculada
AU - Fernández-Gutiérrez, Benjamín
AU - Rodríguez-Rodríguez, Luis
AU - Vicente, Esther
AU - Andreu, José Luis
AU - de Castro, Mónica Fernández
AU - López-Longo, Francisco Javier
AU - Martínez, Lina
AU - Fonollosa, Vicente
AU - Guillén, Alfredo
AU - Castellví, Iván
AU - Espinosa, Gerard
AU - Tolosa, Carlos
AU - Pros, Anna
AU - Carballeira, Mónica Rodríguez
AU - Narváez, Francisco Javier
AU - Rivas, Manel Rubio
AU - Santamaría, Vera Ortiz
AU - Madroñero, Ana Belén
AU - González-Gay, Miguel ángel
AU - Díaz, Bernardino
AU - Trapiella, Luis
AU - Freire, Mayka
AU - Sousa, Adrián
AU - Egurbide, María Victoria
AU - Mateo, Patricia Fanlo
AU - Sáez-Comet, Luis
AU - Díaz, Federico
AU - Hernánde, Vanesa
AU - Beltrán, Emma
AU - Román-Ivorra, José Andrés
AU - Grau, Elena
AU - Sancho, Juan José Alegre
AU - García, Francisco J Blanco
PY - 2016
Y1 - 2016
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.
UR - http://www.scopus.com/inward/record.url?scp=84940943110&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84940943110&partnerID=8YFLogxK
U2 - 10.1136/annrheumdis-2015-208154
DO - 10.1136/annrheumdis-2015-208154
M3 - Article
AN - SCOPUS:84940943110
VL - 75
SP - 1521
EP - 1526
JO - Annals of the Rheumatic Diseases
JF - Annals of the Rheumatic Diseases
SN - 0003-4967
IS - 8
ER -