ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 804

Combined-Phenotype Meta-GWAS in Systemic Sclerosis and Rheumatoid Arthritis Identifies IRF4 As a New Common Susceptibility Locus

Elena Lopez-Isac1, Shervin Assassi2, Carmen Pilar Simeón3, Patricia Carreira4, Norberto Ortego Centeno5, Benjamin Fernandez Gutierrez6, Alejandro Balsa7, Miguel Angel González-Gay8, Lorenzo Beretta9, Claudio Lunardi10, Gianluca Moroncini11, Torsten Witte12, Nicolas Hunzelmann13, Joerg HW Distler14, Gabriela Riekemasten15, Annette HM van der Helm-van Mil16, Jeska K. de Vries-Bouwstra17, Cesar Magro-Checa18, Alexandre E. Voskuyl19, Madelon C. Vonk20, Øyvind Molberg21, Tony Merriman22, Roger Hesselstrand23, Annika Nordin24, Leonid Padyukov25, Ariane L. Herrick26, Stephen Eyre27, Christopher Denton28, Carmen Fonseca29, Timothy R.D.J. Radstake30, Jane Worthington31, Maureen D Mayes2 and Javier Martín1, 1Institute of Parasitology and Biomedicine López-Neyra, IPBLN-CSIC, Granada, Spain, 2Department of Internal Medicine - Rheumatology, University of Texas-McGovern Medical School, Houston, TX, 3Internal Medicine, Hospital Universitari Vall d'Hebron, Barcelona, Spain, 4Department of Rheumatology, Hospital Universitario 12 de Octubre, Madrid, Spain, 5Medicine Department, Hospital Universitario San Cecilio, Granada, Spain, 6Department of Rheumatology, Hospital Clínico San Carlos, Madrid, Spain, 7Department of Rheumatology, Hospital La Paz, Madrid, Spain, 8School of Medicine, University of Cantabria, Santander, Spain, 9Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy, 10Department of Medicine, Università degli Studi di Verona, Verona, Italy, 11Dipartimento di Scienze mediche e Chirurgiche, Università politecnica delle Marche and Ospedali Riuniti, Ancona, Italy, 12Department of Clinical Immunology and Rheumatology, Hannover Medical School, Hannover, Germany, 13Department of Dermatology, University of Cologne, Cologne, Germany, 14Department of Internal Medicine 3 – Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany, 15Department of Rheumatology, University of Lübeck, Luebeck, Germany, 16Rheumatology, Rheumatology, Leiden University Medical Center, Leiden, Netherlands, 17Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands, 18Department of Rheumatology, Leiden University Medical Center, Leiden, Spain, 19Rheumatology, Amsterdam Rheumatology and immunology Center, Location VU University Medical Center, Amsterdam, Netherlands, 20Department of the Rheumatic Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, 21Rheumatology, Oslo University Hospital, Oslo, Norway, 22Department of Biochemistry, University of Otago, Otago, New Zealand, 23Department of Rheumatology, Lund University, Lund, Sweden, 24Department of Rheumatology, Karolinska Institute, Stockholm, Sweden, 25Unit of Rheumatology, Department of Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden, 26Centre for Musculoskeletal Research, University of Manchester, MAHSC, Salford Royal Hospital, Manchester, United Kingdom, 27The University of Manchester, Manchester, United Kingdom, 28Division of Medicine, Centre for Rheumatology and Connective Tissue Disease, University College London, London, United Kingdom, 29Centre for Rheumatology, Royal Free and University College Medical School, London, United Kingdom, 30Laboratory of Translational Immunology, UMC Utrecht, Utrecht, Netherlands, 31Arthritis Research UK Epidemiology Unit, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United Kingdom

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: , ,

Session Information

Date: Sunday, November 13, 2016

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's – Pathogenesis, Animal Models and Genetics - Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Genome-wide association studies (GWASs) have revolutionized our understanding of the genetic component of complex autoimmune diseases (ADs) by the identification of thousands of susceptibility loci associated with autoimmunity. The vast majority of these loci are shared risk factors for at least two or more ADs, pointing to a common genetic background underlying autoimmune processes. One approach that has been developed for the identification of common loci is to perform a combined-phenotype GWAS, that is, to combine genome-wide genotype data from two autoimmune diseases. In the present study we applied this strategy to systematically search for new common loci for systemic sclerosis (SSc) and rheumatoid arthritis (RA), two complex traits that share clinical and immunological features, and a considerable proportion of its genetic background.

Methods: The complete set of individuals enrolled for this study comprised a total of 8,830 SSc patients, 16,870 RA patients and 43,393 controls of European ancestry. First, we performed a meta-analysis combining GWAS datasets of SSc and RA using a strategy that allowed identification of loci with both same-direction and opposing-direction allelic effects. Those SNPs that showed a P-value < 5 x 10-6 in the combined-phenotype analysis and nominal significance in the GWA study for each disease (P-value < 0.05) were followed-up in independent SSc and RA case-control replication cohorts. Subsequently, we performed a meta-analysis of the initial GWAS screening and replication stages. Association tests were performed by the means of logistic regression. Meta-analyses were performed with inverse-variance method based on population specific logistic regression results.

Results: The cross-disease meta-analysis of the GWAS datasets identified several loci with nominal association signals (P-value < 5 x 10-6), which also showed evidence of association in the disease-specific GWAS scan. These loci included several genomic regions not previously reported as shared loci, besides risk factors associated with both diseases in previous studies. The follow-up of the putatively new SSc-RA loci identified IRF4 as a shared risk factor for these two diseases (Pcombined = 3.29 x 10-12). In addition, the analysis of the biological relevance of the known SSc-RA shared loci pointed to the type I interferon and the interleukin 12 signaling pathways as the main common etiopathogenic factors.

Conclusion: The present study has identified a novel shared locus, IRF4, for SSc and RA. The identification of these pleiotropic autoimmunity loci may point to common pathogenic pathways, which ultimately may represent a clinical advantage, thus providing support for drug repositioning.

Disclosure: E. Lopez-Isac, None; S. Assassi, None; C. P. Simeón, None; P. Carreira, None; N. Ortego Centeno, None; B. Fernandez Gutierrez, None; A. Balsa, None; M. A. González-Gay, None; L. Beretta, None; C. Lunardi, None; G. Moroncini, None; T. Witte, None; N. Hunzelmann, None; J. H. Distler, None; G. Riekemasten, None; A. H. van der Helm-van Mil, None; J. K. de Vries-Bouwstra, None; C. Magro-Checa, None; A. E. Voskuyl, None; M. C. Vonk, None; Ø. Molberg, None; T. Merriman, None; R. Hesselstrand, None; A. Nordin, None; L. Padyukov, None; A. L. Herrick, None; S. Eyre, None; C. Denton, GSK, Celgene, Actelion, Bayer, Sanofi, Roche-Genentech, Inventiva, 5,CSL Behring, GSK, Actelion, Roche-Genentech, Inventiva, 2; C. Fonseca, None; T. R. D. J. Radstake, None; J. Worthington, None; M. D. Mayes, None; J. Martín, None.

To cite this abstract in AMA style:

Lopez-Isac E, Assassi S, Simeón CP, Carreira P, Ortego Centeno N, Fernandez Gutierrez B, Balsa A, González-Gay MA, Beretta L, Lunardi C, Moroncini G, Witte T, Hunzelmann N, Distler JH, Riekemasten G, van der Helm-van Mil AH, de Vries-Bouwstra JK, Magro-Checa C, Voskuyl AE, Vonk MC, Molberg Ø, Merriman T, Hesselstrand R, Nordin A, Padyukov L, Herrick AL, Eyre S, Denton C, Fonseca C, Radstake TRDJ, Worthington J, Mayes MD, Martín J. Combined-Phenotype Meta-GWAS in Systemic Sclerosis and Rheumatoid Arthritis Identifies IRF4 As a New Common Susceptibility Locus [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/combined-phenotype-meta-gwas-in-systemic-sclerosis-and-rheumatoid-arthritis-identifies-irf4-as-a-new-common-susceptibility-locus/. Accessed .

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