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.
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.



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.



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.



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.
Institute of Parasitology and Biomedicine López-Neyra CSIC, Granada, Spain.
Elena
E
López-Isac
Institute of Parasitology and Biomedicine López-Neyra CSIC, Granada, Spain.
Jose-Ezequiel
JE
Martín
University of Texas Health Science Center, Houston.
Shervin
S
Assassi
Valle de Hebrón Hospital, Barcelona, Spain.
Carmen P
CP
Simeón
12 de Octubre University Hospital, Madrid, Spain.
Patricia
P
Carreira
Clinic University Hospital, Granada, Spain.
Norberto
N
Ortego-Centeno
Complexo Hospitalario Universitario de Vigo, Vigo, Spain.
Mayka
M
Freire
Hospital General Universitario de Valencia, Valencia, Spain.
Emma
E
Beltrán
Hospital Universitari de Bellvitge, Barcelona, Spain.
Javier
J
Narváez
Hospital Universitari Doctor Peset, Valencia, Spain.
Juan J
JJ
Alegre-Sancho
Hospital Clínico San Carlos, Madrid, Spain.
Benjamín
B
Fernández-Gutiérrez
Hospital Universitario La Paz, Instituto de Investigación Sanitaria La Paz, Madrid, Spain.
Alejandro
A
Balsa
Hospital Universitario La Princesa, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain.
Ana M
AM
Ortiz
University of Cantabria, Santander, Spain.
Miguel A
MA
González-Gay
Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy.
Lorenzo
L
Beretta
Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy.
Alessandro
A
Santaniello
Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy.
Chiara
C
Bellocchi
Università degli Studi di Verona, Verona, Italy.
Claudio
C
Lunardi
Università Politecnica delle Marche and Ospedali Riuniti, Ancona, Italy.
Gianluca
G
Moroncini
Università Politecnica delle Marche and Ospedali Riuniti, Ancona, Italy.
Armando
A
Gabrielli
Hannover Medical School, Hannover, Germany.
Torsten
T
Witte
University of Cologne, Cologne, Germany.
Nicolas
N
Hunzelmann
University of Erlangen-Nuremberg, Erlangen, Germany.
Jörg H W
JH
Distler
University of Lübeck, Lübeck, Germany.
Gabriella
G
Riekemasten
Leiden University Medical Center, Leiden, The Netherlands.
Annette H
AH
van der Helm-van Mil
Leiden University Medical Center, Leiden, The Netherlands.
Jeska
J
de Vries-Bouwstra
Leiden University Medical Center, Leiden, The Netherlands.
Cesar
C
Magro-Checa
VU University Medical Center, Amsterdam, The Netherlands.
Alexandre E
AE
Voskuyl
Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Madelon C
MC
Vonk
Oslo University Hospital Rikshospitalet and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Øyvind
Ø
Molberg
University of Otago, Otago, New Zealand.
Tony
T
Merriman
Lund University, Lund, Sweden.
Roger
R
Hesselstrand
Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
Annika
A
Nordin
Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
Leonid
L
Padyukov
University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
Ariane
A
Herrick
University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
Steve
S
Eyre
University Medical Center Utrecht, Utrecht, The Netherlands.
Bobby P C
BP
Koeleman
Centre for Rheumatology, Royal Free and University College Medical School, London, UK.
Christopher P
CP
Denton
Centre for Rheumatology, Royal Free and University College Medical School, London, UK.
Carmen
C
Fonseca
University Medical Center Utrecht, Utrecht, The Netherlands. Members of the Spanish Scleroderma Group are shown in Appendix A.
Timothy R D J
TR
Radstake
University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
Jane
J
Worthington
University of Texas Health Science Center, Houston.
Maureen D
MD
Mayes
Institute of Parasitology and Biomedicine López-Neyra CSIC, Granada, Spain.
Javier
J
Martín
D001172:Arthritis, Rheumatoid / Q000235:genetics*; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D012307:Risk Factors; D012595:Scleroderma, Systemic / Q000235:genetics*; D000099218:Interferon Regulatory Factor-4
D050835:Interferon Regulatory Factors; D000099218:Interferon Regulatory Factor-4