Risk loci involved in giant cell arteritis susceptibility : a genome-wide association study
Borrego-Yaniz, Gonzalo (Instituto de Parasitología y Biomedicina "López-Neyra")
Ortiz-Fernández, Lourdes (Instituto de Parasitología y Biomedicina "López-Neyra")
Madrid-Paredes, Adela (Hospital Universitario San Cecilio (Granada))
Kerick, Martin (Instituto de Parasitología y Biomedicina "López-Neyra")
Hernández-Rodríguez, José (Hospital Clínic i Provincial de Barcelona)
Mackie, Sarah L. (University of Leeds)
Vaglio, Augusto (Università degli Studi di Firenze)
Castañeda, Santos (Hospital Universitario de la Princesa (Madrid))
Solans, Roser (Universitat Autònoma de Barcelona. Departament de Medicina)
Mestre Torres, Jaume (Universitat Autònoma de Barcelona. Departament de Medicina)
Khalidi, Nader (McMaster University (Canadà))
Langford, Carol (Cleveland Clinic (Cleveland, Estats Units d'Amèrica))
Ytterberg, Steven (Mayo Clinic (Rochester, Estats Units d'Amèrica))
Beretta, Lorenzo (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (Milà, Itàlia))
Govoni, Marcello (University of Ferrara)
Emmi, Giacomo (Monash University)
Cimmino, Marco Amedeo (University of Genova (Itàlia))
Witte, Torsten (Hannover Medical School)
Neumann, Thomas (Jena University Hospital (Alemania))
Holle, Julia (Klinikum Bad Bramstedt and University Hospital of Schleswig Holstein)
Schönau, Verena (Universitätsklinikum Erlangen)
Pugnet, Gregory (Toulouse University Hospital Center)
Papo, Thomas (Université Paris-Cité)
Haroche, Julien (Hospital de la Pitié-Salpêtrière (París, França))
Mahr, Alfred (Centre of Research in Epidemiology and Statistics)
Mouthon, Luc (Université Paris Descartes)
Molberg, Ø. (Oslo University Hospital (Oslo, Noruega))
Diamantopoulos, Andreas P. (Hospital of Southern Norway Trust)
Voskuyl, A.E. (Amsterdam University Medical Centre)
Daikeler, Thomas (University Hospital Basel (Basilea, Suïssa))
Berger, Christoph T. (University Hospital Basel (Basilea, Suïssa))
Molloy, Eamonn S. (St Vincent's University Hospital)
Blockmans, Daniel (University Hospitals Gasthuisberg (Leuven, Bélgica))
van Sleen, Yannick (University of Groningen)
Iles, Mark (University of Leeds)
Sorensen, Louise (University of Leeds)
Luqmani, Raashid (University of Oxford)
Reynolds, Gary (Massachusetts General Hospital (Boston))
Bukhari, Marwan (Lancaster University)
Bhagat, Shweta (Bury Saint Edmunds)
Ortego-Centeno, Norberto (Universidad de Granada)
Brouwer, Elisabeth (University of Groningen)
Lamprecht, Peter (University of Lübeck)
Klapa, Sebastian (University of Lübeck)
Salvarani, Carlo (Azienda USL-IRCCS di Reggio Emilia and Università di Modena e Reggio Emilia)
Merkel, Peter A. (University of Pennsylvania)
Cid, María Cinta (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Gonzalez-Gay, MA. (Universidad de Cantabria)
Morgan, Ann W. (University of Leeds)
Martín, Javier (Instituto de Parasitología y Biomedicina "López-Neyra")
Márquez, Ana (Instituto de Parasitología y Biomedicina "López-Neyra")

Data:	2024
Resum:	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. 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. 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). 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 Research.
Ajuts:	Instituto de Salud Carlos III PI18/00040
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	The Lancet. Rheumatology, Vol. 6 Núm. 6 (June 2024) , p. e374-e383, ISSN 2665-9913

DOI: 10.1016/S2665-9913(24)00064-X
PMID: 38734017

10 p, 673.2 KB

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