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

Elena López-Isac, Jose Ezequiel Martín, Shervin Assassi, Carmen P. Simeón, Patricia Carreira, Norberto Ortego-Centeno, Mayka Freire, Emma Beltrán, Javier Narváez, Juan J. Alegre-Sancho, Benjamín Fernández-Gutiérrez, Alejandro Balsa, Ana M. Ortiz, Miguel A. González-Gay, Lorenzo Beretta, Alessandro Santaniello, Chiara Bellocchi, Claudio Lunardi, Gianluca Moroncini, Armando Gabrielli & 31 others Torsten Witte, Nicolas Hunzelmann, Jörg H W Distler, Gabriella Riekemasten, Annette H. van der Helm-van Mil, Jeska de Vries-Bouwstra, Cesar Magro-Checa, Alexandre E. Voskuyl, Madelon C. Vonk, Øyvind Molberg, Tony Merriman, Roger Hesselstrand, Annika Nordin, Leonid Padyukov, Ariane Herrick, Steve Eyre, Bobby P C Koeleman, Christopher P. Denton, Carmen Fonseca, Timothy R D J Radstake, Jane Worthington, 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, the Spanish Scleroderma Group

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)2338-2344
Number of pages7
JournalArthritis and Rheumatology
Volume68
Issue number9
DOIs
Publication statusPublished - Sep 1 2016

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Systemic Scleroderma
Genome-Wide Association Study
Meta-Analysis
Rheumatoid Arthritis
Metagenome
Interferon Type I
Genetic Loci
Interleukin-12
Sample Size
Autoimmune Diseases
Single Nucleotide Polymorphism
Direction compound
Datasets

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

Cite this

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; Alegre-Sancho, Juan J.; Fernández-Gutiérrez, Benjamín; Balsa, Alejandro; Ortiz, Ana M.; González-Gay, Miguel A.; Beretta, Lorenzo; Santaniello, Alessandro; Bellocchi, Chiara; Lunardi, Claudio; Moroncini, Gianluca; Gabrielli, Armando; Witte, Torsten; Hunzelmann, Nicolas; Distler, Jörg H W; Riekemasten, Gabriella; van der Helm-van Mil, Annette H.; de Vries-Bouwstra, Jeska; Magro-Checa, Cesar; Voskuyl, Alexandre E.; Vonk, Madelon C.; Molberg, Øyvind; Merriman, Tony; Hesselstrand, Roger; Nordin, Annika; Padyukov, Leonid; Herrick, Ariane; Eyre, Steve; Koeleman, Bobby P C; Denton, Christopher P.; Fonseca, Carmen; Radstake, Timothy R D J; Worthington, Jane; 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.; the Spanish Scleroderma Group.

In: Arthritis and Rheumatology, Vol. 68, No. 9, 01.09.2016, p. 2338-2344.

Research output: Contribution to journalArticle

López-Isac, E, Martín, JE, Assassi, S, Simeón, CP, Carreira, P, Ortego-Centeno, N, Freire, M, Beltrán, E, Narváez, J, Alegre-Sancho, JJ, Fernández-Gutiérrez, B, Balsa, A, Ortiz, AM, González-Gay, MA, Beretta, L, Santaniello, A, Bellocchi, C, Lunardi, C, Moroncini, G, Gabrielli, A, Witte, T, Hunzelmann, N, Distler, JHW, Riekemasten, G, van der Helm-van Mil, AH, de Vries-Bouwstra, J, Magro-Checa, C, Voskuyl, AE, Vonk, MC, Molberg, Ø, Merriman, T, Hesselstrand, R, Nordin, A, Padyukov, L, Herrick, A, Eyre, S, Koeleman, BPC, Denton, CP, Fonseca, C, Radstake, TRDJ, Worthington, J, Mayes, MD, Martín, J, Ríos, R, Callejas, JL, Hitos, JAV, Portales, RG, Camps, MT, Fernández-Nebro, A, González-Escribano, MF & the Spanish Scleroderma Group 2016, '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', Arthritis and Rheumatology, vol. 68, no. 9, pp. 2338-2344. https://doi.org/10.1002/art.39730
López-Isac, Elena ; Martín, Jose Ezequiel ; Assassi, Shervin ; Simeón, Carmen P. ; Carreira, Patricia ; Ortego-Centeno, Norberto ; Freire, Mayka ; Beltrán, Emma ; Narváez, Javier ; Alegre-Sancho, Juan J. ; Fernández-Gutiérrez, Benjamín ; Balsa, Alejandro ; Ortiz, Ana M. ; González-Gay, Miguel A. ; Beretta, Lorenzo ; Santaniello, Alessandro ; Bellocchi, Chiara ; Lunardi, Claudio ; Moroncini, Gianluca ; Gabrielli, Armando ; Witte, Torsten ; Hunzelmann, Nicolas ; Distler, Jörg H W ; Riekemasten, Gabriella ; van der Helm-van Mil, Annette H. ; de Vries-Bouwstra, Jeska ; Magro-Checa, Cesar ; Voskuyl, Alexandre E. ; Vonk, Madelon C. ; Molberg, Øyvind ; Merriman, Tony ; Hesselstrand, Roger ; Nordin, Annika ; Padyukov, Leonid ; Herrick, Ariane ; Eyre, Steve ; Koeleman, Bobby P C ; Denton, Christopher P. ; Fonseca, Carmen ; Radstake, Timothy R D J ; Worthington, Jane ; 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. ; the Spanish Scleroderma Group. / 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. In: Arthritis and Rheumatology. 2016 ; Vol. 68, No. 9. pp. 2338-2344.
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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",
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 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.",
author = "Elena L{\'o}pez-Isac and Mart{\'i}n, {Jose Ezequiel} and Shervin Assassi and Sime{\'o}n, {Carmen P.} and Patricia Carreira and Norberto Ortego-Centeno and Mayka Freire and Emma Beltr{\'a}n and Javier Narv{\'a}ez and Alegre-Sancho, {Juan J.} and Benjam{\'i}n Fern{\'a}ndez-Guti{\'e}rrez and Alejandro Balsa and Ortiz, {Ana M.} and Gonz{\'a}lez-Gay, {Miguel A.} and Lorenzo Beretta and Alessandro Santaniello and Chiara Bellocchi and Claudio Lunardi and Gianluca Moroncini and Armando Gabrielli and Torsten Witte and Nicolas Hunzelmann and Distler, {J{\"o}rg H W} and Gabriella Riekemasten and {van der Helm-van Mil}, {Annette H.} and {de Vries-Bouwstra}, Jeska and Cesar Magro-Checa and Voskuyl, {Alexandre E.} and Vonk, {Madelon C.} and {\O}yvind Molberg and Tony Merriman and Roger Hesselstrand and Annika Nordin and Leonid Padyukov and Ariane Herrick and Steve Eyre and Koeleman, {Bobby P C} and Denton, {Christopher P.} and Carmen Fonseca and Radstake, {Timothy R D J} and Jane Worthington 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 {the Spanish Scleroderma Group}",
year = "2016",
month = "9",
day = "1",
doi = "10.1002/art.39730",
language = "English",
volume = "68",
pages = "2338--2344",
journal = "Arthritis and Rheumatology",
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TY - JOUR

T1 - Brief Report

T2 - 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

AU - López-Isac, Elena

AU - Martín, Jose Ezequiel

AU - Assassi, Shervin

AU - Simeón, Carmen P.

AU - Carreira, Patricia

AU - Ortego-Centeno, Norberto

AU - Freire, Mayka

AU - Beltrán, Emma

AU - Narváez, Javier

AU - Alegre-Sancho, Juan J.

AU - Fernández-Gutiérrez, Benjamín

AU - Balsa, Alejandro

AU - Ortiz, Ana M.

AU - González-Gay, Miguel A.

AU - Beretta, Lorenzo

AU - Santaniello, Alessandro

AU - Bellocchi, Chiara

AU - Lunardi, Claudio

AU - Moroncini, Gianluca

AU - Gabrielli, Armando

AU - Witte, Torsten

AU - Hunzelmann, Nicolas

AU - Distler, Jörg H W

AU - Riekemasten, Gabriella

AU - van der Helm-van Mil, Annette H.

AU - de Vries-Bouwstra, Jeska

AU - Magro-Checa, Cesar

AU - Voskuyl, Alexandre E.

AU - Vonk, Madelon C.

AU - Molberg, Øyvind

AU - Merriman, Tony

AU - Hesselstrand, Roger

AU - Nordin, Annika

AU - Padyukov, Leonid

AU - Herrick, Ariane

AU - Eyre, Steve

AU - Koeleman, Bobby P C

AU - Denton, Christopher P.

AU - Fonseca, Carmen

AU - Radstake, Timothy R D J

AU - Worthington, Jane

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 - the Spanish Scleroderma Group

PY - 2016/9/1

Y1 - 2016/9/1

N2 - 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.

AB - 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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