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

被引：42

作者：

Lopez-Isac, Elena ^{[1
]}

Campillo-Davo, Diana ^{[1
]}

Bossini-Castillo, Lara ^{[1
]}

Guerra, Sandra G. ^{[2
]}

Assassi, Shervin ^{[3
]}

Pilar Simeon, Carmen ^{[4
]}

Carreira, Patricia ^{[5
]}

Ortego-Centeno, Norberto ^{[6
]}

Garcia de la Pena, Paloma ^{[7
]}

Beretta, Lorenzo ^{[8
]}

Santaniello, Alessandro ^{[8
]}

Bellocchi, Chiara ^{[8
]}

Lunardi, Claudio ^{[9
]}

Moroncini, Gianluca ^{[10
,11
]}

Gabrielli, Armando ^{[10
,11
]}

Riemekasten, Gabriela ^{[12
,13
]}

Witte, Torsten ^{[14
]}

Hunzelmann, Nicolas ^{[15
]}

Kreuter, Alexander ^{[16
]}

Distler, Jorg H. W. ^{[17
]}

Voskuyl, Alexandre E. ^{[18
]}

de Vries-Bouwstra, Jeska ^{[19
]}

Herrick, Ariane ^{[20
,21
]}

Worthington, Jane ^{[20
,21
]}

Denton, Christopher P. ^{[2
]}

Fonseca, Carmen ^{[2
]}

Radstake, Timothy R. D. J. ^{[22
]}

Mayes, Maureen D. ^{[3
]}

Martin, Javier ^{[1
]}

机构：

[1] CSIC, PTS Granada, Inst Parasitol & Biomed Lopez Neyra, IPBLN, Granada, Spain

[2] Royal Free & Univ Coll Med Sch, Ctr Rheumatol, London, England

[3] Univ Texas Hlth Sci Ctr Houston, Div Rheumatol & Clin Immunogenet, Houston, TX 77030 USA

[4] Valle de Hebron Hosp, Dept Internal Med, Barcelona, Spain

[5] 12 Octubre Univ Hosp, Dept Rheumatol, Madrid, Spain

[6] Clin Univ Hosp, Dept Internal Med, Granada, Spain

[7] Madrid Norte Sanchinarro Hosp, Dept Rheumatol, Madrid, Spain

[8] Fdn IRCCS Ca Granda Osped Maggiore Policlin Maggi, Referral Ctr Syst Autoimmune Dis, Milan, Italy

[9] Univ Verona, Dept Med, Verona, Italy

[10] Univ Politecn Marche, Dipartimento Sci Clin & Mol, Clin Med, Ancona, Italy

[11] Osped Riuniti Bergamo, Ancona, Italy

[12] Charite, Dept Rheumatol & Clin Immunol, Berlin, Germany

[13] German Rheumatism Res Ctr DRFZ, Berlin, Germany

[14] Hannover Med Sch, Dept Clin Immunol, Hannover, Germany

[15] Univ Cologne, Dept Dermatol, Cologne, Germany

[16] HELIOS St Elisabeth Hosp, Dept Dermatol Venereol & Allergol, Oberhausen, Germany

[17] Univ Erlangen Nurnberg, Inst Clin Immunol, Dept Internal Med, Erlangen, Germany

[18] Vrije Univ Amsterdam, Med Ctr, Dept Rheumatol, Amsterdam, Netherlands

[19] Leiden Univ, Med Ctr, Dept Rheumatol, Leiden, Netherlands

[20] Univ Manchester, Manchester Acad Hlth Sci Ctr, Ctr Musculoskeletal Res, Manchester, Lancs, England

[21] Univ Manchester, Manchester Acad Hlth Sci Ctr, NIHR Manchester Musculoskeletal Biomed Res Unit, Manchester, Lancs, England

[22] Univ Med Ctr Utrecht, Dept Immunol, Lab Translat Immunol, Dept Rheumatol & Clin Immunol, Utrecht, Netherlands

来源：

ANNALS OF THE RHEUMATIC DISEASES | 2016年 / 75卷 / 08期

关键词：

GENOME-WIDE ASSOCIATION; INTERLEUKIN-12/23; MONOCLONAL-ANTIBODY; TYROSINE KINASE 2; RHEUMATOID-ARTHRITIS; LUPUS-ERYTHEMATOSUS; DOUBLE-BLIND; DISEASE; IDENTIFICATION; PSORIASIS; USTEKINUMAB;

D O I：

10.1136/annrheumdis-2015-208154

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：1521 / 1526

页数：6

共 40 条

[1] A method and server for predicting damaging missense mutations [J].

Adzhubei, Ivan A. ;

Schmidt, Steffen ;

Peshkin, Leonid ;

Ramensky, Vasily E. ;

Gerasimova, Anna ;

Bork, Peer ;

Kondrashov, Alexey S. ;

Sunyaev, Shamil R. .

NATURE METHODS, 2010, 7 (04) :248-249

[2] A map of human genome variation from population-scale sequencing [J].

Altshuler, David ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Collins, Francis S. ;

De la Vega, Francisco M. ;

Donnelly, Peter ;

Egholm, Michael ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Knoppers, Bartha M. ;

Lander, Eric S. ;

Lehrach, Hans ;

Mardis, Elaine R. ;

McVean, Gil A. ;

Nickerson, DebbieA. ;

Peltonen, Leena ;

Schafer, Alan J. ;

Sherry, Stephen T. ;

Wang, Jun ;

Wilson, Richard K. ;

Gibbs, Richard A. ;

Deiros, David ;

Metzker, Mike ;

Muzny, Donna ;

Reid, Jeff ;

Wheeler, David ;

Wang, Jun ;

Li, Jingxiang ;

Jian, Min ;

Li, Guoqing ;

Li, Ruiqiang ;

Liang, Huiqing ;

Tian, Geng ;

Wang, Bo ;

Wang, Jian ;

Wang, Wei ;

Yang, Huanming ;

Zhang, Xiuqing ;

Zheng, Huisong ;

Lander, Eric S. ;

Altshuler, David L. ;

Ambrogio, Lauren ;

Bloom, Toby ;

Cibulskis, Kristian ;

Fennell, Tim J. ;

Gabriel, Stacey B. .

NATURE, 2010, 467 (7319) :1061-1073

[3]

Anon MC, 1980, ARTHRITIS RHEUM, V23, P581

[4] Genetics of scleroderma: implications for personalized medicine? [J].

Assassi, Shervin ;

Radstake, Timothy R. D. J. ;

Mayes, Maureen D. ;

Martin, Javier .

BMC MEDICINE, 2013, 11

[5] A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations [J].

Bossini-Castillo, Lara ;

Martin, Jose-Ezequiel ;

Broen, Jasper ;

Gorlova, Olga ;

Simeon, Carmen P. ;

Beretta, Lorenzo ;

Vonk, Madelon C. ;

Luis Callejas, Jose ;

Castellvi, Ivan ;

Carreira, Patricia ;

Jose Garcia-Hernandez, Francisco ;

Fernandez Castro, Monica ;

Coenen, Marieke J. H. ;

Riemekasten, Gabriela ;

Witte, Torsten ;

Hunzelmann, Nicolas ;

Kreuter, Alexander ;

Distler, Joerg H. W. ;

Koeleman, Bobby P. ;

Voskuyl, Alexandre E. ;

Schuerwegh, Annemie J. ;

Palm, Oyvind ;

Hesselstrand, Roger ;

Nordin, Annika ;

Airo, Paolo ;

Lunardi, Claudio ;

Scorza, Raffaella ;

Shiels, Paul ;

van Laar, Jacob M. ;

Herrick, Ariane ;

Worthington, Jane ;

Denton, Christopher ;

Tan, Filemon K. ;

Arnett, Frank C. ;

Agarwal, Sandeep K. ;

Assassi, Shervin ;

Fonseca, Carmen ;

Mayes, Maureen D. ;

Radstake, Timothy R. D. J. ;

Martin, Javier .

HUMAN MOLECULAR GENETICS, 2012, 21 (04) :926-933

[6] Seven newly identified loci for autoimmune thyroid disease [J].

Cooper, Jason D. ;

Simmonds, Matthew J. ;

Walker, Neil M. ;

Burren, Oliver ;

Brand, Oliver J. ;

Guo, Hui ;

Wallace, Chris ;

Stevens, Helen ;

Coleman, Gillian ;

Franklyn, Jayne A. ;

Todd, John A. ;

Gough, Stephen C. L. .

HUMAN MOLECULAR GENETICS, 2012, 21 (23) :5202-5208

[7] Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci [J].

Cortes, Adrian ;

Hadler, Johanna ;

Pointon, Jenny P. ;

Robinson, Philip C. ;

Karaderi, Tugce ;

Leo, Paul ;

Cremin, Katie ;

Pryce, Karena ;

Harris, Jessica ;

Lee, Seunghun ;

Joo, Kyung Bin ;

Shim, Seung-Cheol ;

Weisman, Michael ;

Ward, Michael ;

Zhou, Xiaodong ;

Garchon, Henri-Jean ;

Chiocchia, Gilles ;

Nossent, Johannes ;

Lie, Benedicte A. ;

Forre, Oystein ;

Tuomilehto, Jaakko ;

Laiho, Kari ;

Jiang, Lei ;

Liu, Yu ;

Wu, Xin ;

Bradbury, Linda A. ;

Elewaut, Dirk ;

Burgos-Vargas, Ruben ;

Stebbings, Simon ;

Appleton, Louise ;

Farrah, Claire ;

Lau, Jonathan ;

Kenna, Tony J. ;

Haroon, Nigil ;

Ferreira, Manuel A. ;

Yang, Jian ;

Mulero, Juan ;

Fernandez-Sueiro, Jose Luis ;

Gonzalez-Gay, Miguel A. ;

Lopez-Larrea, Carlos ;

Deloukas, Panos ;

Donnelly, Peter ;

Bowness, Paul ;

Gafney, Karl ;

Gaston, Hill ;

Gladman, Dafna D. ;

Rahman, Proton ;

Maksymowych, Walter P. ;

Xu, Huji ;

Crusius, J. Bart A. .

NATURE GENETICS, 2013, 45 (07) :730-+

[8] Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility [J].

Couturier, Nicolas ;

Bucciarelli, Florence ;

Nurtdinov, Ramil N. ;

Debouverie, Marc ;

Lebrun-Frenay, Christine ;

Defer, Gilles ;

Moreau, Thibault ;

Confavreux, Christian ;

Vukusic, Sandra ;

Cournu-Rebeix, Isabelle ;

Goertsches, Robert H. ;

Zettl, Uwe K. ;

Comabella, Manuel ;

Montalban, Xavier ;

Rieckmann, Peter ;

Weber, Frank ;

Mueller-Myhsok, Bertram ;

Edan, Gilles ;

Fontaine, Bertrand ;

Mars, Lennart T. ;

Saoudi, Abdelhadi ;

Oksenberg, Jorge R. ;

Clanet, Michel ;

Liblau, Roland S. ;

Brassat, David .

BRAIN, 2011, 134 :693-703

[9] TYK2 Protein-Coding Variants Protect against Rheumatoid Arthritis and Autoimmunity, with No Evidence of Major Pleiotropic Effects on Non-Autoimmune Complex Traits [J].

Diogo, Dorothee ;

Bastarache, Lisa ;

Liao, Katherine P. ;

Graham, Robert R. ;

Fulton, Robert S. ;

Greenberg, Jeffrey D. ;

Eyre, Steve ;

Bowes, John ;

Cui, Jing ;

Lee, Annette ;

Pappas, Dimitrios A. ;

Kremer, Joel M. ;

Barton, Anne ;

Coenen, Marieke J. H. ;

Franke, Barbara ;

Kiemeney, Lambertus A. ;

Mariette, Xavier ;

Richard-Miceli, Corrine ;

Canhao, Helena ;

Fonseca, Joao E. ;

de Vries, Niek ;

Tak, Paul P. ;

Crusius, J. Bart A. ;

Nurmohamed, Michael T. ;

Kurreeman, Fina ;

Mikuls, Ted R. ;

Okada, Yukinori ;

Stahl, Eli A. ;

Larson, David E. ;

Deluca, Tracie L. ;

O'Laughlin, Michelle ;

Fronick, Catrina C. ;

Fulton, Lucinda L. ;

Kosoy, Roman ;

Ransom, Michael ;

Bhangale, Tushar R. ;

Ortmann, Ward ;

Cagan, Andrew ;

Gainer, Vivian ;

Karlson, Elizabeth W. ;

Kohane, Isaac ;

Murphy, Shawn N. ;

Martin, Javier ;

Zhernakova, Alexandra ;

Klareskog, Lars ;

Padyukov, Leonid ;

Worthington, Jane ;

Mardis, Elaine R. ;

Seldin, Michael F. ;

Gregersen, Peter K. .

PLOS ONE, 2015, 10 (04)

[10] High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis [J].

Eyre, Steve ;

Bowes, John ;

Diogo, Dorothee ;

Lee, Annette ;

Barton, Anne ;

Martin, Paul ;

Zhernakova, Alexandra ;

Stahl, Eli ;

Viatte, Sebastien ;

McAllister, Kate ;

Amos, Christopher I. ;

Padyukov, Leonid ;

Toes, Rene E. M. ;

Huizinga, Tom W. J. ;

Wijmenga, Cisca ;

Trynka, Gosia ;

Franke, Lude ;

Westra, Harm-Jan ;

Alfredsson, Lars ;

Hu, Xinli ;

Sandor, Cynthia ;

de Bakker, Paul I. W. ;

Davila, Sonia ;

Khor, Chiea Chuen ;

Heng, Khai Koon ;

Andrews, Robert ;

Edkins, Sarah ;

Hunt, Sarah E. ;

Langford, Cordelia ;

Symmons, Deborah ;

Concannon, Pat ;

Onengut-Gumuscu, Suna ;

Rich, Stephen S. ;

Deloukas, Panos ;

Gonzalez-Gay, Miguel A. ;

Rodriguez-Rodriguez, Luis ;

Arlsetig, Lisbeth ;

Martin, Javier ;

Rantapaa-Dahlqvist, Solbritt ;

Plenge, Robert M. ;

Raychaudhuri, Soumya ;

Klareskog, Lars ;

Gregersen, Peter K. ;

Worthington, Jane .

NATURE GENETICS, 2012, 44 (12) :1336-1340

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