Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study
et al.
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Tipo de documento: | artigo |
| Estado: | Versão publicada |
| Data de publicação: | 2024 |
| País: | España |
| Recursos: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositório: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/372621 |
| Acesso em linha: | http://hdl.handle.net/10261/372621 |
| Access Level: | Acceso aberto |
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Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study |
| title |
Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study |
| spellingShingle |
Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study Borrego Yaniz, Gonzalo |
| title_short |
Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study |
| title_full |
Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study |
| title_fullStr |
Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study |
| title_full_unstemmed |
Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study |
| title_sort |
Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study |
| dc.creator.none.fl_str_mv |
Borrego Yaniz, Gonzalo Ortiz-Fernández, Lourdes Madrid-Paredes, Adela Kerick, Martin Hernández-Rodríguez, José Mackie, Sarah Vaglio, Augusto Castañeda, Santos Solans, Roser Khalidi, Nader Langford, Carol Ytterberg, Steven R. Beretta, Lorenzo Govoni, Marcelo Emmi, Giacomo Cimmino, Marco A. Witte, Torsten Neumann, Thomas Holle, Julia Schönau, Verena Pugnet, Gregory Papo, Thomas Haroche, Julien Mahr, Alfred Mouthon, Luc Molberg, Oyvind Diamantopoulos, Andreas P. Voskuyl, Alexandre E. Daikeler, Thomas Berger, Christoph Molloy, Eamonn Blockmans, Daniel Ortego-Centeno, Norberto Brouwer, Elisabeth Lamprecht, Peter Klapa, Sebastian Salvarani, Carlo Merkel, Peter A. Cid, María C. González-Gay, Miguel A. Morgan, Ann W. Martín, Javier Márquez, Ana Spanish GCA Study Group UK GCA Consortium Vasculitis Clinical Research Consortium |
| author |
Borrego Yaniz, Gonzalo |
| author_facet |
Borrego Yaniz, Gonzalo Ortiz-Fernández, Lourdes Madrid-Paredes, Adela Kerick, Martin Hernández-Rodríguez, José Mackie, Sarah Vaglio, Augusto Castañeda, Santos Solans, Roser Khalidi, Nader Langford, Carol Ytterberg, Steven R. Beretta, Lorenzo Govoni, Marcelo Emmi, Giacomo Cimmino, Marco A. Witte, Torsten Neumann, Thomas Holle, Julia Schönau, Verena Pugnet, Gregory Papo, Thomas Haroche, Julien Mahr, Alfred Mouthon, Luc Molberg, Oyvind Diamantopoulos, Andreas P. Voskuyl, Alexandre E. Daikeler, Thomas Berger, Christoph Molloy, Eamonn Blockmans, Daniel Ortego-Centeno, Norberto Brouwer, Elisabeth Lamprecht, Peter Klapa, Sebastian Salvarani, Carlo Merkel, Peter A. Cid, María C. González-Gay, Miguel A. Morgan, Ann W. Martín, Javier Márquez, Ana Spanish GCA Study Group UK GCA Consortium Vasculitis Clinical Research Consortium |
| author_role |
author |
| author2 |
Ortiz-Fernández, Lourdes Madrid-Paredes, Adela Kerick, Martin Hernández-Rodríguez, José Mackie, Sarah Vaglio, Augusto Castañeda, Santos Solans, Roser Khalidi, Nader Langford, Carol Ytterberg, Steven R. Beretta, Lorenzo Govoni, Marcelo Emmi, Giacomo Cimmino, Marco A. Witte, Torsten Neumann, Thomas Holle, Julia Schönau, Verena Pugnet, Gregory Papo, Thomas Haroche, Julien Mahr, Alfred Mouthon, Luc Molberg, Oyvind Diamantopoulos, Andreas P. Voskuyl, Alexandre E. Daikeler, Thomas Berger, Christoph Molloy, Eamonn Blockmans, Daniel Ortego-Centeno, Norberto Brouwer, Elisabeth Lamprecht, Peter Klapa, Sebastian Salvarani, Carlo Merkel, Peter A. Cid, María C. González-Gay, Miguel A. Morgan, Ann W. Martín, Javier Márquez, Ana Spanish GCA Study Group UK GCA Consortium Vasculitis Clinical Research Consortium |
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author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
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Instituto de Salud Carlos III Ministerio de Ciencia e Innovación (España) National Institute for Health and Care Research (US) Medical Research Council (UK) European Commission Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72] |
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et al. |
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2024 |
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2024 2024 2024 |
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info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Publisher's version info:eu-repo/semantics/publishedVersion |
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article |
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http://hdl.handle.net/10261/372621 |
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http://hdl.handle.net/10261/372621 |
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Inglés |
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Elsevier |
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Elsevier |
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Risk loci involved in giant cell arteritis susceptibility: a genome-wide association studyBorrego Yaniz, GonzaloOrtiz-Fernández, LourdesMadrid-Paredes, AdelaKerick, MartinHernández-Rodríguez, JoséMackie, SarahVaglio, AugustoCastañeda, SantosSolans, RoserKhalidi, NaderLangford, CarolYtterberg, Steven R.Beretta, LorenzoGovoni, MarceloEmmi, GiacomoCimmino, Marco A.Witte, TorstenNeumann, ThomasHolle, JuliaSchönau, VerenaPugnet, GregoryPapo, ThomasHaroche, JulienMahr, AlfredMouthon, LucMolberg, OyvindDiamantopoulos, Andreas P.Voskuyl, Alexandre E.Daikeler, ThomasBerger, ChristophMolloy, EamonnBlockmans, DanielOrtego-Centeno, NorbertoBrouwer, ElisabethLamprecht, PeterKlapa, SebastianSalvarani, CarloMerkel, Peter A.Cid, María C.González-Gay, Miguel A.Morgan, Ann W.Martín, JavierMárquez, AnaSpanish GCA Study GroupUK GCA ConsortiumVasculitis Clinical Research Consortiumet al.[Background] Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci.[Methods] We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings.[Findings] We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10–8; OR 1·19 [95% CI 1·12–1·26]) and VTN (rs704; p=2·75 × 10–9; OR 0·84 [0·79–0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10–8; OR 1·18 [1·12–1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15–3·82]; p=1·73 × 10–13).[Interpretation] We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis.Institute of Health Carlos III, Spanish Ministry of Science and Innovation, UK Medical Research Council, and National Institute for Health and Care ResearchMCC reports support from the Spanish Ministry of Science and Innovation (PID2020-114909RB-I00), EU/EFPIA/Innovative Medicines Initiative 2 Joint Undertaking Immune-Image grant no 831514. LO-F was supported by a Juan de la Cierva Incorporación fellowship (IJC2019-040746-I), funded by MCIN/AEI/10.13039/501100011033.Peer reviewedElsevierInstituto de Salud Carlos IIIMinisterio de Ciencia e Innovación (España)National Institute for Health and Care Research (US)Medical Research Council (UK)European CommissionConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202420242024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/372621reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/EC/H2020/831514info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-114909RB-I00info:eu-repo/grantAgreement/AEI//IJC2019-040746-IThe underlying dataset has been published as supplementary material of the article in the publisher platform at DOI 10.1016/S2665-9913(24)00064-Xhttps://doi.org/10.1016/ S2665-9913(24)00064-XSíinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3726212026-05-22T06:33:51Z |
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