Influence of TYK2 in systemic sclerosis susceptibility: A new locus in the IL-12 pathway

Elena López-Isac, Diana Campillo-Davo, Lara Bossini-Castillo, Sandra G. Guerra, Shervin Assassi, Carmen Pilar Simeón, Patricia Carreira, Norberto Ortego-Centeno, Paloma García de la Peña, Lorenzo Beretta, Alessandro Santaniello, Chiara Bellocchi, Claudio Lunardi, Gianluca Moroncini, Armando Gabrielli, Gabriela Riemekasten, Torsten Witte, Nicolas Hunzelmann, Alexander Kreuter, Jörg H W DistlerAlexandre E. Voskuyl, Jeska de Vries-Bouwstra, Ariane Herrick, Jane Worthington, Christopher P. Denton, Carmen Fonseca, Timothy R D J Radstake, Maureen D. Mayes, Javier Martín, Raquel Ríos, Jose Luis Callejas, José Antonio Vargas Hitos, Rosa García Portales, María Teresa Camps, Antonio Fernández-Nebro, María F. González-Escribano, Francisco José García-Hernández, M. Jesús Castillo, M. ángeles Aguirre, Inmaculada Gómez-Gracia, Benjamín Fernández-Gutiérrez, Luis Rodríguez-Rodríguez, Esther Vicente, José Luis Andreu, Mónica Fernández de Castro, Francisco Javier López-Longo, Lina Martínez, Vicente Fonollosa, Alfredo Guillén, Iván Castellví, Gerard Espinosa, Carlos Tolosa, Anna Pros, Mónica Rodríguez Carballeira, Francisco Javier Narváez, Manel Rubio Rivas, Vera Ortiz Santamaría, Ana Belén Madroñero, Miguel ángel González-Gay, Bernardino Díaz, Luis Trapiella, Mayka Freire, Adrián Sousa, María Victoria Egurbide, Patricia Fanlo Mateo, Luis Sáez-Comet, Federico Díaz, Vanesa Hernánde, Emma Beltrán, José Andrés Román-Ivorra, Elena Grau, Juan José Alegre Sancho, Francisco J Blanco García

Research output: Contribution to journalArticle

14 Citations (Scopus)

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 languageEnglish
Pages (from-to)1521-1526
Number of pages6
JournalAnnals of the Rheumatic Diseases
Volume75
Issue number8
DOIs
Publication statusPublished - 2016

Fingerprint

Systemic Scleroderma
Interleukin-12
Logistics
Genes
Polymorphism
Protein Kinases
Screening
Nucleotides
Logistic Models
Netherlands
Spain
Italy
Autoimmune Diseases
Single Nucleotide Polymorphism
Germany
Meta-Analysis
Genome

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Allergy

Cite this

López-Isac, E., Campillo-Davo, D., Bossini-Castillo, L., Guerra, S. G., Assassi, S., Simeón, C. P., ... García, F. J. B. (2016). Influence of TYK2 in systemic sclerosis susceptibility: A new locus in the IL-12 pathway. Annals of the Rheumatic Diseases, 75(8), 1521-1526. https://doi.org/10.1136/annrheumdis-2015-208154

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 journalArticle

López-Isac, E, Campillo-Davo, D, Bossini-Castillo, L, Guerra, SG, Assassi, S, Simeón, CP, Carreira, P, Ortego-Centeno, N, de la Peña, PG, Beretta, L, Santaniello, A, Bellocchi, C, Lunardi, C, Moroncini, G, Gabrielli, A, Riemekasten, G, Witte, T, Hunzelmann, N, Kreuter, A, Distler, JHW, Voskuyl, AE, de Vries-Bouwstra, J, Herrick, A, Worthington, J, Denton, CP, Fonseca, C, Radstake, TRDJ, Mayes, MD, Martín, J, Ríos, R, Callejas, JL, Hitos, JAV, Portales, RG, Camps, MT, Fernández-Nebro, A, González-Escribano, MF, García-Hernández, FJ, Castillo, MJ, Aguirre, MÁ, Gómez-Gracia, I, Fernández-Gutiérrez, B, Rodríguez-Rodríguez, L, Vicente, E, Andreu, JL, de Castro, MF, López-Longo, FJ, Martínez, L, Fonollosa, V, Guillén, A, Castellví, I, Espinosa, G, Tolosa, C, Pros, A, Carballeira, MR, Narváez, FJ, Rivas, MR, Santamaría, VO, Madroñero, AB, González-Gay, MÁ, Díaz, B, Trapiella, L, Freire, M, Sousa, A, Egurbide, MV, Mateo, PF, Sáez-Comet, L, Díaz, F, Hernánde, V, Beltrán, E, Román-Ivorra, JA, Grau, E, Sancho, JJA & García, FJB 2016, 'Influence of TYK2 in systemic sclerosis susceptibility: A new locus in the IL-12 pathway', Annals of the Rheumatic Diseases, vol. 75, no. 8, pp. 1521-1526. https://doi.org/10.1136/annrheumdis-2015-208154
López-Isac E, Campillo-Davo D, Bossini-Castillo L, Guerra SG, Assassi S, Simeón CP et al. Influence of TYK2 in systemic sclerosis susceptibility: A new locus in the IL-12 pathway. Annals of the Rheumatic Diseases. 2016;75(8):1521-1526. https://doi.org/10.1136/annrheumdis-2015-208154
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. / Influence of TYK2 in systemic sclerosis susceptibility : A new locus in the IL-12 pathway. In: Annals of the Rheumatic Diseases. 2016 ; Vol. 75, No. 8. pp. 1521-1526.
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title = "Influence of TYK2 in systemic sclerosis susceptibility: A new locus in the IL-12 pathway",
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.",
author = "Elena L{\'o}pez-Isac and Diana Campillo-Davo and Lara Bossini-Castillo and Guerra, {Sandra G.} and Shervin Assassi and Sime{\'o}n, {Carmen Pilar} and Patricia Carreira and Norberto Ortego-Centeno and {de la Pe{\~n}a}, {Paloma Garc{\'i}a} and Lorenzo Beretta and Alessandro Santaniello and Chiara Bellocchi and Claudio Lunardi and Gianluca Moroncini and Armando Gabrielli and Gabriela Riemekasten and Torsten Witte and Nicolas Hunzelmann and Alexander Kreuter and Distler, {J{\"o}rg H W} and Voskuyl, {Alexandre E.} and {de Vries-Bouwstra}, Jeska and Ariane Herrick and Jane Worthington and Denton, {Christopher P.} and Carmen Fonseca and Radstake, {Timothy R D J} and Mayes, {Maureen D.} and Javier Mart{\'i}n and Raquel R{\'i}os and Callejas, {Jose Luis} and Hitos, {Jos{\'e} Antonio Vargas} and Portales, {Rosa Garc{\'i}a} and Camps, {Mar{\'i}a Teresa} and Antonio Fern{\'a}ndez-Nebro and Gonz{\'a}lez-Escribano, {Mar{\'i}a F.} and Garc{\'i}a-Hern{\'a}ndez, {Francisco Jos{\'e}} and Castillo, {M. Jes{\'u}s} and Aguirre, {M. {\'a}ngeles} and Inmaculada G{\'o}mez-Gracia and Benjam{\'i}n Fern{\'a}ndez-Guti{\'e}rrez and Luis Rodr{\'i}guez-Rodr{\'i}guez and Esther Vicente and Andreu, {Jos{\'e} Luis} and {de Castro}, {M{\'o}nica Fern{\'a}ndez} and L{\'o}pez-Longo, {Francisco Javier} and Lina Mart{\'i}nez and Vicente Fonollosa and Alfredo Guill{\'e}n and Iv{\'a}n Castellv{\'i} and Gerard Espinosa and Carlos Tolosa and Anna Pros and Carballeira, {M{\'o}nica Rodr{\'i}guez} and Narv{\'a}ez, {Francisco Javier} and Rivas, {Manel Rubio} and Santamar{\'i}a, {Vera Ortiz} and Madro{\~n}ero, {Ana Bel{\'e}n} and Gonz{\'a}lez-Gay, {Miguel {\'a}ngel} and Bernardino D{\'i}az and Luis Trapiella and Mayka Freire and Adri{\'a}n Sousa and Egurbide, {Mar{\'i}a Victoria} and Mateo, {Patricia Fanlo} and Luis S{\'a}ez-Comet and Federico D{\'i}az and Vanesa Hern{\'a}nde and Emma Beltr{\'a}n and Rom{\'a}n-Ivorra, {Jos{\'e} Andr{\'e}s} and Elena Grau and Sancho, {Juan Jos{\'e} Alegre} and Garc{\'i}a, {Francisco J Blanco}",
year = "2016",
doi = "10.1136/annrheumdis-2015-208154",
language = "English",
volume = "75",
pages = "1521--1526",
journal = "Annals of the Rheumatic Diseases",
issn = "0003-4967",
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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.

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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 -