Author:
Acosta-Herrera Marialbert,Kerick Martin,González-Serna David,Wijmenga Cisca,Franke Andre,Gregersen Peter K,Padyukov Leonid,Worthington Jane,Vyse Timothy James,Alarcón-Riquelme Marta Eugenia,Mayes Maureen D,Martin Javier, ,
Abstract
ObjectiveImmune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies.MethodsWe meta-analysed ~6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases.ResultsOur analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study.ConclusionsWe have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs.
Funder
Spanish Ministry of Economy Industry and Competitiveness
Supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences
The Regional Ministry of Innovation, Science and Technologies of the Andalusian Regional Government
EU/EFPIA Innovative Medicines Initiative
Juan de la Cierva Formacion fellowship
Subject
General Biochemistry, Genetics and Molecular Biology,Immunology,Immunology and Allergy,Rheumatology
Cited by
80 articles.
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