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 - Tập 68 Số 9 - Trang 2338-2344 - 2016
Elena López‐Isac1, Javier Martı́n1, Shervin Assassi2, Carmen Pilar Simeón‐Aznar3, Patrícia Carreira4, Norbérto Ortego-Centeno5, M. Freire6, E. Beltrán7, Javier Narváez8, Juan José Alegre Sancho9, Antonio Fernández‐Nebro10, Alejandro Balsa11, Ana M. Ortiz12, Miguel Á. González‐Gay13, Lorenzo Beretta14,15, Alessandro Santaniello14, Chiara Bellocchi14, Claudio Lunardi16, Gianluca Moroncini17, Tianlu Li17, Torsten Witte18, Nicolas Hunzelmann19, Jörg H. W. Distler20, Gabriella Riekemasten21, Annette H M van der Helm–van Mil22, Jeska de Vries‐Bouwstra23, César Magro‐Checa23, Alexandre E. Voskuyl23, Alfredo Castillo24, Øyvind Molberg25, Tony R. Merriman26, Roger Hesselstrand27, Annica Nordin28, Leonid Padyukov28, Ariane L. Herrick29, Stephen E. Epstein29, Christopher P. Denton30, Carmen Fonseca30, Timothy R. D. J. Radstake31, Jane Worthington31, Maureen D. Mayes32
1Institute of Parasitology and Biomedicine López‐Neyra CSIC Granada Spain
2University of Texas Health Science Center, Houston
3Valle de Hebrón Hospital Barcelona Spain
4“12 de Octubre” University Hospital, Madrid, Spain
5Clinic University Hospital Granada Spain
6Complexo Hospitalario Universitario de Vigo, Vigo, Spain
7Hospital General Universitario de Valencia, Valencia, Spain
8Hospital Universitari de Bellvitge, Barcelona, Spain
9Hospital Universitari Doctor Peset Valencia Spain
10Hospital Clínico San Carlos, Madrid, Spain
11Hospital Universitario La Paz, Instituto de Investigación Sanitaria La Paz Madrid Spain
12Hospital Universitario La Princesa, Instituto de Investigación Sanitaria La Princesa Madrid Spain
13University of Cantabria, Santander, Spain
14Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy
15University of CantabriaSantander Spain
16Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di MilanoMilan Italy
17Università Politecnica delle Marche and Ospedali Riuniti Ancona Italy
18Hannover Medical School, Hannover, Germany
19Hannover Medical SchoolHannover Germany
20University of Erlangen–Nuremberg, Erlangen, Germany
21University of Lübeck, Lübeck, Germany
22Leiden University Medical Center, Leiden, The Netherlands.
23Leiden University Medical CenterLeiden, the Netherlands.
24Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
25Oslo University Hospital Rikshospitalet and Institute of Clinical Medicine, University of Oslo Oslo Norway
26Oslo University Hospital Rikshospitalet and Institute of Clinical Medicine, University of OsloOslo Norway
27University of Otago, Otago, New Zealand
28Karolinska University Hospital / Karolinska Institutet, Stockholm, Sweden
29University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
30Centre for Rheumatology, Royal Free and University College Medical School, London, UK
31University Medical Center Utrecht, Utrecht, The Netherlands. Members of the Spanish Scleroderma Group are shown in Appendix A.
32University of Manchester, Manchester Academic Health Science CentreManchester UK

Tóm tắt

ObjectiveSystemic 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.MethodsThe 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.ResultsThis 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.ConclusionThis 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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Arthritis and Rheumatology

Tập 68 Số 9

2338-2344

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