IRF4 Newly Identified as a Common Susceptibility Locus for Systemic Sclerosis and Rheumatoid Arthritis in a Cross-Disease Meta-Analysis of Genome-Wide Association Studies

被引：42

作者：

Lopez-Isac, Elena ^{[1
]}

Martin, Jose-Ezequiel ^{[1
]}

Assassi, Shervin ^{[2
]}

Simeon, Carmen P. ^{[3
]}

Carreira, Patricia ^{[4
]}

Ortego-Centeno, Norberto ^{[5
]}

Freire, Mayka ^{[6
]}

Beltran, Emma ^{[7
]}

Narvaez, Javier ^{[8
]}

Alegre-Sancho, Juan J. ^{[9
]}

Fernandez-Gutierrez, Benjamin ^{[10
]}

Balsa, Alejandro ^{[11
]}

Ortiz, Ana M. ^{[12
]}

Gonzalez-Gay, Miguel A. ^{[13
]}

Beretta, Lorenzo ^{[14
]}

Santaniello, Alessandro ^{[14
]}

Bellocchi, Chiara ^{[14
]}

Lunardi, Claudio ^{[15
]}

Moroncini, Gianluca ^{[16
,17
]}

Gabrielli, Armando ^{[16
,17
]}

Witte, Torsten ^{[18
]}

Hunzelmann, Nicolas ^{[19
]}

Distler, Jorg H. W. ^{[20
]}

Riekemasten, Gabriella ^{[21
]}

van der Helm-Van Mil, Annette H. ^{[22
]}

de Vries-Bouwstra, Jeska ^{[22
]}

Magro-Checa, Cesar ^{[22
]}

Voskuyl, Alexandre E. ^{[23
]}

Vonk, Madelon C. ^{[24
]}

Molberg, Oyvind ^{[25
,26
]}

Merriman, Tony ^{[27
]}

Hesselstrand, Roger ^{[28
]}

Nordin, Annika ^{[29
]}

Padyukov, Leonid ^{[29
]}

Herrick, Ariane ^{[30
]}

Eyre, Steve ^{[30
]}

Koeleman, Bobby P. C. ^{[31
]}

Denton, Christopher P. ^{[32
,33
]}

Fonseca, Carmen ^{[32
,33
]}

Radstake, Timothy R. D. J. ^{[34
]}

Worthington, Jane ^{[30
]}

Mayes, Maureen D. ^{[2
]}

Martin, Javier ^{[1
]}

机构：

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

[2] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA

[3] Valle Hebron Hosp, Barcelona, Spain

[4] 12 Octubre Univ Hosp, Madrid, Spain

[5] Clin Univ Hosp, Granada, Spain

[6] Complexo Hosp Univ Vigo, Vigo, Spain

[7] Hosp Gen Univ Valencia, Valencia, Spain

[8] Hosp Univ Bellvitge, Barcelona, Spain

[9] Hosp Univ Doctor Peset, Valencia, Spain

[10] Hosp Clin San Carlos, Madrid, Spain

[11] Hosp Univ La Paz, Inst Invest Sanitaria La Paz, Madrid, Spain

[12] Hosp Univ La Princesa, Inst Invest Sanitaria La Princesa, Madrid, Spain

[13] Univ Cantabria, Santander, Spain

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

[15] Univ Verona, Verona, Italy

[16] Univ Politecn Marche, Ancona, Italy

[17] Osped Riuniti, Ancona, Italy

[18] Hannover Med Sch, Hannover, Germany

[19] Univ Cologne, Cologne, Germany

[20] Univ Erlangen Nurnberg, Erlangen, Germany

[21] Univ Lubeck, Lubeck, Germany

[22] Leiden Univ, Med Ctr, Leiden, Netherlands

[23] Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands

[24] Radboud Univ Nijmegen, Med Ctr, Nijmegen, Netherlands

[25] Oslo Univ Hosp Rikshosp, Oslo, Norway

[26] Univ Oslo, Inst Clin Med, Oslo, Norway

[27] Univ Otago, Otago, New Zealand

[28] Lund Univ, Lund, Sweden

[29] Karolinska Univ Hosp, Karolinska Inst, Stockholm, Sweden

[30] Univ Manchester, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England

[31] Univ Med Ctr Utrecht, Utrecht, Netherlands

[32] Royal Free, Ctr Rheumatol, London, England

[33] UCL, Sch Med, London, England

[34] Univ Med Ctr Utrecht, Utrecht, Netherlands

来源：

ARTHRITIS & RHEUMATOLOGY | 2016年 / 68卷 / 09期

关键词：

AUTOIMMUNE-DISEASES; PATHWAYS;

D O I：

10.1002/art.39730

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Objective. Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that have similar clinical and immunologic characteristics. To date, several shared SSc-RA genetic loci have been identified independently. The aim of the current study was to systematically search for new common SSc-RA loci through an interdisease meta-genome-wide association (meta-GWAS) strategy. Methods. The study was designed as a meta-analysis combining GWAS data sets of patients with SSc and patients with RA, using a strategy that allowed identification of loci with both same-direction and opposite-direction allelic effects. The top single-nucleotide polymorphisms were followed up in independent SSc and RA case-control cohorts. This allowed an increase in the sample size to a total of 8,830 patients with SSc, 16,870 patients with RA, and 43,393 healthy controls. Results. This cross-disease meta-analysis of the GWAS data sets identified several loci with nominal association signals (P<5 x 10(-6)) that also showed evidence of association in the disease-specific GWAS scans. These loci included several genomic regions not previously reported as shared loci, as well as several risk factors that were previously found to be associated with both diseases. Follow-up analyses of the putatively new SSc-RA loci identified IRF4 as a shared risk factor for these 2 diseases (P-combined=3.29 x 10(-12)). Analysis of the biologic relevance of the known SSc-RA shared loci identified the type I interferon and interleukin-12 signaling pathways as the main common etiologic factors. Conclusion. This study identified a novel shared locus, IRF4, for the risk of SSc and RA, and highlighted the usefulness of a cross-disease GWAS meta-analysis strategy in the identification of common risk loci.

引用

页码：2338 / 2344

页数：7

共 15 条

[1] Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20 [J].

Bahlo, Melanie ;

Booth, David R. ;

Broadley, Simon A. ;

Brown, Matthew A. ;

Foote, Simon J. ;

Griffiths, Lyn R. ;

Kilpatrick, Trevor J. ;

Lechner-Scott, Jeanette ;

Moscato, Pablo ;

Perreau, Victoria M. ;

Rubio, Justin P. ;

Scott, Rodney J. ;

Stankovich, Jim ;

Stewart, Graeme J. ;

Taylor, Bruce V. ;

Wiley, James ;

Clarke, Glynnis ;

Cox, Mathew B. ;

Csurhes, Peter A. ;

Danoy, Patrick ;

Drysdale, Karen ;

Field, Judith ;

Foote, Simon J. ;

Greer, Judith M. ;

Guru, Preethi ;

Hadler, Johanna ;

McMorran, Brendan J. ;

Jensen, Cathy J. ;

Johnson, Laura J. ;

McCallum, Ruth ;

Merriman, Marilyn ;

Merriman, Tony ;

Pryce, Karen ;

Tajouri, Lotfi ;

Wilkins, Ella J. ;

Browning, Brian L. ;

Browning, Sharon R. ;

Perera, Devindri ;

Butzkueven, Helmut ;

Carroll, William M. ;

Chapman, Caron ;

Kermode, Allan G. ;

Marriott, Mark ;

Mason, Deborah ;

Heard, Robert N. ;

Pender, Michael P. ;

Slee, Mark ;

Tubridy, Niall ;

Willoughby, Ernest .

NATURE GENETICS, 2009, 41 (07) :824-U84

[2] Dual regulation of IRF4 function in T and B cells is required for the coordination of T-B cell interactions and the prevention of autoimmunity [J].

Biswas, Partha S. ;

Gupta, Sanjay ;

Stirzaker, Roslynn A. ;

Kumar, Varsha ;

Jessberger, Rolf ;

Lu, Theresa T. ;

Bhagat, Govind ;

Pernis, Alessandra B. .

JOURNAL OF EXPERIMENTAL MEDICINE, 2012, 209 (03) :581-596

[3] Immunogenetics of systemic sclerosis: Defining heritability, functional variants and shared-autoimmunity pathways [J].

Bossini-Castillo, Lara ;

Lopez-Isac, Elena ;

Martin, Javier .

JOURNAL OF AUTOIMMUNITY, 2015, 64 :53-65

[4] Systemic sclerosis at the crossroad of polyautoimmunity [J].

Elhai, Muriel ;

Avouac, Jerome ;

Kahan, Andre ;

Allanore, Yannick .

AUTOIMMUNITY REVIEWS, 2013, 12 (11) :1052-1057

[5] A Meta-Analysis of Genome-Wide Association Scans Identifies IL18RAP, PTPN2, TAGAP, and PUS10 As Shared Risk Loci for Crohn's Disease and Celiac Disease [J].

Festen, Eleonora A. M. ;

Goyette, Philippe ;

Green, Todd ;

Boucher, Gabrielle ;

Beauchamp, Claudine ;

Trynka, Gosia ;

Dubois, Patrick C. ;

Lagace, Caroline ;

Stokkers, Pieter C. F. ;

Hommes, Daan W. ;

Barisani, Donatella ;

Palmieri, Orazio ;

Annese, Vito ;

van Heel, David A. ;

Weersma, Rinse K. ;

Daly, Mark J. ;

Wijmenga, Cisca ;

Rioux, John D. .

PLOS GENETICS, 2011, 7 (01)

[6] A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association Studies [J].

Howie, Bryan N. ;

Donnelly, Peter ;

Marchini, Jonathan .

PLOS GENETICS, 2009, 5 (06)

[7] A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci [J].

Martin, Jose-Ezequiel ;

Assassi, Shervin ;

Diaz-Gallo, Lina-Marcela ;

Broen, Jasper C. ;

Simeon, Carmen P. ;

Castellvi, Ivan ;

Vicente-Rabaneda, Esther ;

Fonollosa, Vicente ;

Ortego-Centeno, Norberto ;

Gonzalez-Gay, Miguel A. ;

Espinosa, Gerard ;

Carreira, Patricia ;

Camps, Mayte ;

Sabio, Jose M. ;

D'alfonso, Sandra ;

Vonk, Madelon C. ;

Voskuyl, Alexandre E. ;

Schuerwegh, Annemie J. ;

Kreuter, Alexander ;

Witte, Torsten ;

Riemekasten, Gabriella ;

Hunzelmann, Nicolas ;

Airo, Paolo ;

Beretta, Lorenzo ;

Scorza, Raffaella ;

Lunardi, Claudio ;

Van Laar, Jacob ;

Chee, Meng May ;

Worthington, Jane ;

Herrick, Arianne ;

Denton, Christopher ;

Fonseca, Carmen ;

Tan, Filemon K. ;

Arnett, Frank ;

Zhou, Xiaodong ;

Reveille, John D. ;

Gorlova, Olga ;

Koeleman, Bobby P. C. ;

Radstake, Timothy R. D. J. ;

Vyse, Timothy ;

Mayes, Maureen D. ;

Alarcon-Riquelme, Marta E. ;

Martin, Javier .

HUMAN MOLECULAR GENETICS, 2013, 22 (19) :4021-4029

[8] Identification of CSK as a systemic sclerosis genetic risk factor through Genome Wide Association Study follow-up [J].

Martin, Jose-Ezequiel ;

Broen, Jasper C. ;

David Carmona, F. ;

Teruel, Maria ;

Simeon, Carmen P. ;

Vonk, Madelon C. ;

van 't Slot, Ruben ;

Rodriguez-Rodriguez, Luis ;

Vicente, Esther ;

Fonollosa, Vicente ;

Ortego-Centeno, Norberto ;

Gonzalez-Gay, Miguel A. ;

Garcia-Hernandez, Francisco J. ;

Garcia de la Pena, Paloma ;

Carreira, Patricia ;

Voskuyl, Alexandre E. ;

Schuerwegh, Annemie J. ;

van Riel, Piet L. C. M. ;

Kreuter, Alexander ;

Witte, Torsten ;

Riemekasten, Gabriella ;

Airo, Paolo ;

Scorza, Raffaella ;

Lunardi, Claudio ;

Hunzelmann, Nicolas ;

Distler, Joerg H. W. ;

Beretta, Lorenzo ;

van Laar, Jacob ;

Chee, Meng May ;

Worthington, Jane ;

Herrick, Ariane ;

Denton, Christopher ;

Tan, Filemon K. ;

Arnett, Frank C. ;

Assassi, Shervin ;

Fonseca, Carmen ;

Mayes, Maureen D. ;

Radstake, Timothy R. D. J. ;

Koeleman, Bobby P. C. ;

Martin, Javier .

HUMAN MOLECULAR GENETICS, 2012, 21 (12) :2825-2835

[9] Genetics of rheumatoid arthritis contributes to biology and drug discovery [J].

Okada, Yukinori ;

Wu, Di ;

Trynka, Gosia ;

Raj, Towfique ;

Terao, Chikashi ;

Ikari, Katsunori ;

Kochi, Yuta ;

Ohmura, Koichiro ;

Suzuki, Akari ;

Yoshida, Shinji ;

Graham, Robert R. ;

Manoharan, Arun ;

Ortmann, Ward ;

Bhangale, Tushar ;

Denny, Joshua C. ;

Carroll, Robert J. ;

Eyler, Anne E. ;

Greenberg, Jeffrey D. ;

Kremer, Joel M. ;

Pappas, Dimitrios A. ;

Jiang, Lei ;

Yin, Jian ;

Ye, Lingying ;

Su, Ding-Feng ;

Yang, Jian ;

Xie, Gang ;

Keystone, Ed ;

Westra, Harm-Jan ;

Esko, Tonu ;

Metspalu, Andres ;

Zhou, Xuezhong ;

Gupta, Namrata ;

Mirel, Daniel ;

Stahl, Eli A. ;

Diogo, Dorothee ;

Cui, Jing ;

Liao, Katherine ;

Guo, Michael H. ;

Myouzen, Keiko ;

Kawaguchi, Takahisa ;

Coenen, Marieke J. H. ;

van Riel, Piet L. C. M. ;

van de laar, Mart A. F. J. ;

Guchelaar, Henk-Jan ;

Huizinga, Tom W. J. ;

Dieude, Philippe ;

Mariette, Xavier ;

Bridges, S. Louis, Jr. ;

Zhernakova, Alexandra ;

Toes, Rene E. M. .

NATURE, 2014, 506 (7488) :376-+

[10] Genetic insights into common pathways and complex relationships among immune-mediated diseases [J].

Parkes, Miles ;

Cortes, Adrian ;

van Heel, David A. ;

Brown, Matthew A. .

NATURE REVIEWS GENETICS, 2013, 14 (09) :661-673

← 1 2 →