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Ann Rheum Dis. 2019 Mar;78(3):311-319. doi: 10.1136/annrheumdis-2018-214127. Epub 2018 Dec 20.

Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases.

Author information

1
Institute of Parasitology and Biomedicine López-Neyra, IPBLN-CSIC, PTS Granada, Granada, Spain m.acostaherrera@ipb.csic.es javiermartin@ipb.csic.es.
2
Institute of Parasitology and Biomedicine López-Neyra, IPBLN-CSIC, PTS Granada, Granada, Spain.
3
Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
4
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
5
Robert S Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, New York, USA.
6
Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
7
Manchester NIHR Biomedical Research Centre, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
8
Division of Genetics and Molecular Medicine, King's College London, London, UK.
9
Division of Immunology, Infection and Inflammatory Disease, King's College London, London, UK.
10
Centre for Genomics and Oncological Research (GENYO), Pfizer-University of Granada-Andalusian Regional Government, Granada, Spain.
11
Department of Internal Medicine, Division of Rheumatology, The University of Texas Health Science Center-Houston, Houston, Texas, USA.
#
Contributed equally

Abstract

OBJECTIVE:

Immune-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.

METHODS:

We 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.

RESULTS:

Our 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.

CONCLUSIONS:

We 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.

KEYWORDS:

autoimmune diseases; autoimmunity; gene polymorphism

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