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Arthritis Rheumatol. 2016 Sep;68(9):2338-44. doi: 10.1002/art.39730.

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.

Author information

1
Institute of Parasitology and Biomedicine López-Neyra CSIC, Granada, Spain.
2
University of Texas Health Science Center, Houston.
3
Valle de Hebrón Hospital, Barcelona, Spain.
4
12 de Octubre University Hospital, Madrid, Spain.
5
Clinic University Hospital, Granada, Spain.
6
Complexo Hospitalario Universitario de Vigo, Vigo, Spain.
7
Hospital General Universitario de Valencia, Valencia, Spain.
8
Hospital Universitari de Bellvitge, Barcelona, Spain.
9
Hospital Universitari Doctor Peset, Valencia, Spain.
10
Hospital Clínico San Carlos, Madrid, Spain.
11
Hospital Universitario La Paz, Instituto de Investigación Sanitaria La Paz, Madrid, Spain.
12
Hospital Universitario La Princesa, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain.
13
University of Cantabria, Santander, Spain.
14
Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy.
15
Università degli Studi di Verona, Verona, Italy.
16
Università Politecnica delle Marche and Ospedali Riuniti, Ancona, Italy.
17
Hannover Medical School, Hannover, Germany.
18
University of Cologne, Cologne, Germany.
19
University of Erlangen-Nuremberg, Erlangen, Germany.
20
University of Lübeck, Lübeck, Germany.
21
Leiden University Medical Center, Leiden, The Netherlands.
22
VU University Medical Center, Amsterdam, The Netherlands.
23
Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
24
Oslo University Hospital Rikshospitalet and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
25
University of Otago, Otago, New Zealand.
26
Lund University, Lund, Sweden.
27
Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
28
University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
29
University Medical Center Utrecht, Utrecht, The Netherlands.
30
Centre for Rheumatology, Royal Free and University College Medical School, London, UK.
31
University Medical Center Utrecht, Utrecht, The Netherlands. Members of the Spanish Scleroderma Group are shown in Appendix A.

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.

PMID:
27111665
PMCID:
PMC5530728
DOI:
10.1002/art.39730
[Indexed for MEDLINE]
Free PMC Article

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