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Abstract
Objective I mmune-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 similar to 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
Immunology, General Biochemistry, Genetics and Molecular Biology, Immunology and Allergy, Rheumatology, ASSOCIATION, VARIANTS, ARTHRITIS, SCLEROSIS, MULTIPLE, PROTEIN, PATHOGENESIS, GENETICS, COMPLEX, COMMON

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MLA
Acosta-Herrera, Marialbert et al. “Genome-wide Meta-analysis Reveals Shared New Loci in Systemic Seropositive Rheumatic Diseases.” ANNALS OF THE RHEUMATIC DISEASES 78.3 (2019): 311–319. Print.
APA
Acosta-Herrera, M., Kerick, M., González-Serna, D., Wijmenga, C., Franke, A., Gregersen, P. K., Padyukov, L., et al. (2019). Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases. ANNALS OF THE RHEUMATIC DISEASES, 78(3), 311–319.
Chicago author-date
Acosta-Herrera, Marialbert, Martin Kerick, David González-Serna, Cisca Wijmenga, Andre Franke, Peter K Gregersen, Leonid Padyukov, et al. 2019. “Genome-wide Meta-analysis Reveals Shared New Loci in Systemic Seropositive Rheumatic Diseases.” Annals of the Rheumatic Diseases 78 (3): 311–319.
Chicago author-date (all authors)
Acosta-Herrera, Marialbert, Martin Kerick, David González-Serna, Cisca Wijmenga, Andre Franke, Peter K Gregersen, Leonid Padyukov, Jane Worthington, Timothy James Vyse, Marta Eugenia Alarcón-Riquelme, Maureen D Mayes, Javier Martin, the Scleroderma Genetics Consortium, Vanessa Smith, Filip De Keyser, and Elfride De Baere. 2019. “Genome-wide Meta-analysis Reveals Shared New Loci in Systemic Seropositive Rheumatic Diseases.” Annals of the Rheumatic Diseases 78 (3): 311–319.
Vancouver
1.
Acosta-Herrera M, Kerick M, González-Serna D, Wijmenga C, Franke A, Gregersen PK, et al. Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases. ANNALS OF THE RHEUMATIC DISEASES. 2019;78(3):311–9.
IEEE
[1]
M. Acosta-Herrera et al., “Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases,” ANNALS OF THE RHEUMATIC DISEASES, vol. 78, no. 3, pp. 311–319, 2019.
@article{8586743,
  abstract     = {Objective I mmune-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 similar to 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.},
  author       = {Acosta-Herrera, Marialbert and Kerick, Martin and González-Serna, David and Wijmenga, Cisca and Franke, Andre and Gregersen, Peter K and Padyukov, Leonid and Worthington, Jane and Vyse, Timothy James and Alarcón-Riquelme, Marta Eugenia and Mayes, Maureen D and Martin, Javier and Scleroderma Genetics Consortium, the and Smith, Vanessa and De Keyser, Filip and De Baere, Elfride},
  issn         = {0003-4967},
  journal      = {ANNALS OF THE RHEUMATIC DISEASES},
  keywords     = {Immunology,General Biochemistry,Genetics and Molecular Biology,Immunology and Allergy,Rheumatology,ASSOCIATION,VARIANTS,ARTHRITIS,SCLEROSIS,MULTIPLE,PROTEIN,PATHOGENESIS,GENETICS,COMPLEX,COMMON},
  language     = {eng},
  number       = {3},
  pages        = {311--319},
  title        = {Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases},
  url          = {http://dx.doi.org/10.1136/annrheumdis-2018-214127},
  volume       = {78},
  year         = {2019},
}

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