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Brief Report : 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

López-Isac, Elena; Martín, Jose Ezequiel; Assassi, Shervin; Simeón, Carmen P.; Carreira, Patricia; Ortego-Centeno, Norberto; Freire, Mayka; Beltrán, Emma; Narváez, Javier and Alegre-Sancho, Juan J., et al. (2016) In Arthritis and Rheumatology 68(9). p.2338-2344
Abstract

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... (More)

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 × 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 (Pcombined = 3.29 × 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.

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published
subject
keywords
GWAS, Rheumatoid Arthritis , IRF4, SYSTEMIC SCLEROSIS
in
Arthritis and Rheumatology
volume
68
issue
9
pages
7 pages
publisher
Wiley-Blackwell
external identifiers
  • scopus:84983503786
  • wos:000383498800035
ISSN
2326-5191
DOI
10.1002/art.39730
language
English
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yes
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d5fa7c4f-87c1-4abe-b5d1-84993d4eaac8
date added to LUP
2016-09-21 09:42:07
date last changed
2017-04-18 13:24:21
@article{d5fa7c4f-87c1-4abe-b5d1-84993d4eaac8,
  abstract     = {<p>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 &lt; 5 × 10<sup>−6</sup>) 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<sub>combined</sub> = 3.29 × 10<sup>−12</sup>). 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.</p>},
  author       = {López-Isac, Elena and Martín, Jose Ezequiel and Assassi, Shervin and Simeón, Carmen P. and Carreira, Patricia and Ortego-Centeno, Norberto and Freire, Mayka and Beltrán, Emma and Narváez, Javier and Alegre-Sancho, Juan J. and Fernández-Gutiérrez, Benjamín and Balsa, Alejandro and Ortiz, Ana M. and González-Gay, Miguel A. and Beretta, Lorenzo and Santaniello, Alessandro and Bellocchi, Chiara and Lunardi, Claudio and Moroncini, Gianluca and Gabrielli, Armando and Witte, Torsten and Hunzelmann, Nicolas and Distler, Jörg H W and Riekemasten, Gabriella and van der Helm-van Mil, Annette H. and de Vries-Bouwstra, Jeska and Magro-Checa, Cesar and Voskuyl, Alexandre E. and Vonk, Madelon C. and Molberg, Øyvind and Merriman, Tony and Hesselstrand, Roger and Nordin, Annika and Padyukov, Leonid and Herrick, Ariane and Eyre, Steve and Koeleman, Bobby P C and Denton, Christopher P. and Fonseca, Carmen and Radstake, Timothy R D J and Worthington, Jane and Mayes, Maureen D. and Martín, Javier and Ríos, Raquel and Callejas, Jose Luis and Hitos, José Antonio Vargas and Portales, Rosa García and Camps, María Teresa and Fernández-Nebro, Antonio and González-Escribano, María F. and García-Hernández, Francisco José and Castillo, Ma Jesús and Ángeles Aguirre, Ma and Gómez-Gracia, Inmaculada and Rodríguez-Rodríguez, Luis and Peña, Paloma García de la and Vicente, Esther and Andreu, José Luis and de Castro, Mónica Fernández and López-Longo, Francisco Javier and Martínez, Lina and Fonollosa, Vicente and Guillén, Alfredo and Castellví, Iván and Espinosa, Gerard and Tolosa, Carlos and Pros, Anna and Carballeira, Mónica Rodríguez and Narváez, Francisco Javier and Rivas, Manel Rubio and Ortiz-Santamaría, Vera and Madroñero, Ana Belén and Díaz, Bernardino and Trapiella, Luis and Sousa, Adrián and Egurbide, María Victoria and Mateo, Patricia Fanlo and Sáez-Comet, Luis and Díaz, Federico and Hernández, Vanesa and Beltrán, Emma and Román-Ivorra, José Andrés and Grau, Elena and Alegre-Sancho, Juan José and Blanco García, Francisco J. and Oreiro, Natividad},
  issn         = {2326-5191},
  keyword      = {GWAS,Rheumatoid Arthritis ,IRF4,SYSTEMIC SCLEROSIS},
  language     = {eng},
  month        = {09},
  number       = {9},
  pages        = {2338--2344},
  publisher    = {Wiley-Blackwell},
  series       = {Arthritis and Rheumatology},
  title        = {Brief Report : 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},
  url          = {http://dx.doi.org/10.1002/art.39730},
  volume       = {68},
  year         = {2016},
}