Acosta-Herrera, Marialbert, Kerick, Martin, Gonzalez-Serna, David, Wijmenga, Cisca ORCID: 0000-0002-5635-1614, Franke, Andre, Gregersen, Peter K., Padyukov, Leonid, Worthington, Jane, Vyse, Timothy James, Eugenia Alarcon-Riquelme, Marta, Mayes, Maureen D., Martin, Javier ORCID: 0000-0002-2202-0622, Miller, Frederick W., Chen, Wei, O'Hanlon, Terrance P., Cooper, Robert G., Vencovsky, Jiri ORCID: 0000-0002-0851-0713, Rider, Lisa G., Danko, Katalin, Wedderburn, Lucy R., Lundberg, Ingrid E., Pachman, Lauren M., Reed, Ann M., Ytterberg, Steven R., Selva-O'Callaghan, Albert ORCID: 0000-0003-2823-9761, Radstake, Timothy R., Isenberg, David A., Chinoy, Hector, Ollier, William E. R., Scheet, Paul, Peng, Bo, Lee, Annette, Lamb, Janine A., Amos, Christopher I., Denton, Christopher, Hilton-Jones, David, Plotz, Paul H., Varsani, Hemlata, Radstake, Timothy R. D. J., Gorlova, Olga, Rueda, Blanca, Martin, Jose-Ezequiel, Alizadeh, Behrooz Z., Palomino-Morales, Rogelio, Coenen, Marieke J., Vonk, Madelon C., Voskuyl, Alexandre E., Scheurwegh, Annemie J., Broen, Jasper C., van Riel, Piet L. C. M., van 't Slot, Ruben, Italiaander, Annet, Ophoff, Roel A., Riemekasten, Gabriela, Hunzelmann, Nico, Simeon, Carmen P., Ortego-Centeno, Norberto ORCID: 0000-0003-2325-0937, Gonzalez-Gay, Miguel A., Gonzalez-Escribano, Maria F., Airo, Paolo, van Laar, Jaap, Herrick, Ariane, Hesselstrand, Roger, Smith, Vanessa, de Keyser, Filip, Houssiau, Fredric, Chee, Meng May, Madhok, Rajan, Shiels, Paul, Westhovens, Rene, Kreuter, Alexander, Kiener, Hans, de Baere, Elfride, Witte, Torsten, Klareskog, Lars, Beretta, Lorenzo ORCID: 0000-0002-6529-6258, Scorza, Rafaella, Lie, Benedicte A., Hoffman-Vold, Anna-Maria, Carreira, Patricia, Varga, John, Hinchcliff, Monique, Lee, Annette T., Ying, Jun, Han, Younghun, Weng, Shih-Feng, Wigley, Fredrick M., Hummers, Laura, Nelson, J. Lee, Agarwal, Sandeep K., Assassi, Shervin, Gourh, Pravitt, Tan, Filemon K., Koeleman, Bobby P. C. and Arnett, Frank C. (2019). Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases. Ann. Rheum. Dis., 78 (3). S. 311 - 320. LONDON: BMJ PUBLISHING GROUP. ISSN 1468-2060

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Acosta-Herrera, MarialbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kerick, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gonzalez-Serna, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wijmenga, CiscaUNSPECIFIEDorcid.org/0000-0002-5635-1614UNSPECIFIED
Franke, AndreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gregersen, Peter K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Padyukov, LeonidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Worthington, JaneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vyse, Timothy JamesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eugenia Alarcon-Riquelme, MartaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mayes, Maureen D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martin, JavierUNSPECIFIEDorcid.org/0000-0002-2202-0622UNSPECIFIED
Miller, Frederick W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, WeiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
O'Hanlon, Terrance P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cooper, Robert G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vencovsky, JiriUNSPECIFIEDorcid.org/0000-0002-0851-0713UNSPECIFIED
Rider, Lisa G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Danko, KatalinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wedderburn, Lucy R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lundberg, Ingrid E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pachman, Lauren M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reed, Ann M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ytterberg, Steven R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Selva-O'Callaghan, AlbertUNSPECIFIEDorcid.org/0000-0003-2823-9761UNSPECIFIED
Radstake, Timothy R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Isenberg, David A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chinoy, HectorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ollier, William E. R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheet, PaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peng, BoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lee, AnnetteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lamb, Janine A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Amos, Christopher I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Denton, ChristopherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hilton-Jones, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Plotz, Paul H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Varsani, HemlataUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Radstake, Timothy R. D. J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gorlova, OlgaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rueda, BlancaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martin, Jose-EzequielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alizadeh, Behrooz Z.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Palomino-Morales, RogelioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Coenen, Marieke J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vonk, Madelon C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Voskuyl, Alexandre E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheurwegh, Annemie J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Broen, Jasper C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Riel, Piet L. C. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van 't Slot, RubenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Italiaander, AnnetUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ophoff, Roel A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riemekasten, GabrielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hunzelmann, NicoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Simeon, Carmen P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ortego-Centeno, NorbertoUNSPECIFIEDorcid.org/0000-0003-2325-0937UNSPECIFIED
Gonzalez-Gay, Miguel A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gonzalez-Escribano, Maria F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Airo, PaoloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Laar, JaapUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herrick, ArianeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hesselstrand, RogerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smith, VanessaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Keyser, FilipUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Houssiau, FredricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chee, Meng MayUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Madhok, RajanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shiels, PaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Westhovens, ReneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kreuter, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kiener, HansUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Baere, ElfrideUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Witte, TorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klareskog, LarsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beretta, LorenzoUNSPECIFIEDorcid.org/0000-0002-6529-6258UNSPECIFIED
Scorza, RafaellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lie, Benedicte A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoffman-Vold, Anna-MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carreira, PatriciaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Varga, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hinchcliff, MoniqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lee, Annette T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ying, JunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Han, YounghunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weng, Shih-FengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wigley, Fredrick M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hummers, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nelson, J. LeeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Agarwal, Sandeep K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Assassi, ShervinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gourh, PravittUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tan, Filemon K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koeleman, Bobby P. C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arnett, Frank C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-154507
DOI: 10.1136/annrheumdis-2018-214127
Journal or Publication Title: Ann. Rheum. Dis.
Volume: 78
Number: 3
Page Range: S. 311 - 320
Date: 2019
Publisher: BMJ PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1468-2060
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ASSOCIATION; VARIANTS; ARTHRITIS; SCLEROSIS; MULTIPLE; PROTEIN; PATHOGENESIS; GENETICS; COMPLEX; COMMONMultiple languages
RheumatologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15450

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