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

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

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.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Arthritis, Rheumatoid / genetics*
  • Arthritis, Rheumatoid / immunology
  • European Continental Ancestry Group / genetics
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Lim Kinases / immunology
  • Lupus Erythematosus, Systemic / genetics*
  • Lupus Erythematosus, Systemic / immunology
  • Male
  • Membrane Proteins / immunology
  • Myositis / genetics*
  • Myositis / immunology
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci / genetics*
  • Quantitative Trait Loci / immunology
  • Repressor Proteins / immunology
  • Rheumatic Diseases / genetics*
  • Rheumatic Diseases / immunology
  • Scleroderma, Systemic / genetics*
  • Scleroderma, Systemic / immunology
  • alpha Karyopherins / immunology

Substances

  • KPNA4 protein, human
  • Membrane Proteins
  • NAB1 protein, human
  • PRR12 protein, human
  • Repressor Proteins
  • alpha Karyopherins
  • LIMK1 protein, human
  • Lim Kinases