Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status
Lyons, Paul A. (Uniit))
Peters, James E. (Health Data Research UK)
Alberici, Federico (University of Milano)
Liley, James (Cambridge Institute of Public Health)
Coulson, Richard M. R. (University of Cambridge School of Clinical Medicine. University of Cambridge)
Astle, William (NHS Blood and Transplant)
Baldini, Chiara (University of Pisa)
Bonatti, Francesco (University Hospital of Parma)
Cid, María Cinta (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Elding, Heather (Wellcome Trust Sanger Institute (Regne Unit))
Emmi, Giacomo (University of Firenze)
Epplen, Jörg (Ruhr University Bochum)
Guillevin, Loïc (Hôpital Cochin)
Jayne, David R. W. (University of Cambridge School of Clinical Medicine)
Jiang, Tao (University of Cambridge)
Gunnarsson, Iva (Karolinska University Hospital and Karolinska Institutet (Suècia))
Lamprecht, Peter (University of Lübeck)
Leslie, Stephen (Data Science. Murdoch Children's Research Institute)
Little, Mark A. (Tallaght Hospital)
Martorana, Davide (University Hospital of Parma)
Moosig, Frank (Rheumazentrum Schleswig-Holstein Mitte)
Neumann, Thomas (Department of Rheumatology. Immunology and Rehabilitation. Cantonal Hospital St. Gallen)
Ohlsson, Sophie (Department of Nephrology. Division of Clinical Sciences. Lund University)
Quickert, Stefan (Department of Internal Medicine 4 (Gastroenterology. Hepatology. and Infectious Diseases). Jena University Hospital)
Ramirez, Giuseppe A. (Unit of Immunology. Rheumatology. Allergy and Rare Diseases. Università Vita Salute San Raffaele and IRCCS Ospedale San Raffaele)
Rewerska, Barbara (Jagiellonian University Medical College)
Schett, George (Department of Internal Medicine 3. Rheumatology and Immunology. Friedrich Alexander University Erlangen-Nuremberg and Universitatsklinikum Erlangen)
Sinico, Renato A. (Università degli Studi di Milano-Bicocca)
Szczeklik, Wojciech (Jagiellonian University Medical College)
Tesar, Vladimir (Charles University)
Vukcevic, Damjan (Murdoch Children's Research Institute)
Akil, Mohammed (Sheffield Royal Hallamshire Hospital)
Barratt, Jonathan (University of Leicester)
Basu, Neil (University of Glasgow)
Butterworth, Adam (University of Cambridge)
Bruce, Ian (The University of Manchester)
Clarkson, Michael (Cork University Hospital)
Conlon, Niall (St James' Hospital Dublin)
DasGupta, Bhaskar (Southend University Hospital)
Doulton, Timothy W. R. (EKent and Canterbury Hospital)
Espígol-Frigolé, Georgina (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Flossmann, Oliver (Royal Berkshire Hospital NHS Trust)
Gabrielli, Armando (Ospedali Riuniti-Università)
Gasior, Jolanta (University Hospital. Department of allergy and immunology)
Gregorini, Gina (Nephrology Unit. Spedali Civili)
Guida, Giuseppe (ASL TO2 Birago di Vische Hospital)
Hernández Rodríguez, José (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Hruskova, Zdenka (Charles University)
Hudson, Amy (Data Science. Murdoch Children's Research Institute)
Knight, Ann (Department of Medical Sciences. Uppsala University)
Lanyon, Peter (Nottingham University Hospitals NHS Trust (Regne Unit))
Luqmani, Raashid (Nuffield Orthopaedic Centre)
Magliano, Malgorzata (Stoke Mandeville Hospital)
Manfredi, Angelo A. (Università Vita Salute San Raffaele and IRCCS Ospedale San Raffaele)
Marguerie, Christopher (South Warwickshire NHS Foundation Trust)
Maritati, Federica (University of Firenze)
Marvisi, Chiara (University of Firenze)
McHugh, Neil J. (Royal National Hospital for Rheumatic Disease)
Molloy, Eaminn (St Vincent's Hospital Dublin)
Motyer, Allan (University of Melbourne)
Mukhtyar, Chetan (Norfolk and Norwich University Hospital)
Padyukov, Leonid (Karolinska University Hospital and Karolinska Institutet (Suècia))
Pesci, Alberto (University of Milano Bicocca)
Prieto-Gonzalez, Sergio (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Ramentol-Sintas, Marc (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Reis, Petra (Friedrich Alexander University Erlangen-Nuremberg)
Roccatello, Dario (University of Torino)
Rovere-Querini, Patrizia (Jena University Hospital (Alemanya))
Salvarani, Carlo (Università di Modena e Reggio Emilia)
Santarsia, Francesca (University Hospital of Parma)
Solans, Roser (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Soranzo, Nicole (University of Cambridge)
Taylor, Jo (Dorset County Hospital)
Wessels, Julie (Royal Stoke University Hospital)
Zwerina, Jochen (Friedrich Alexander University Erlangen-Nuremberg and Universitatsklinikum Erlangen)
Terrier, Benjamin (Service de Médecine Interne. Hôpital Cochin)
Watts, Richard A. (Norwich Medical School. University of East Anglia)
Vaglio, Augusto (University of Firenze)
Holle, Julia U. (Rheumazentrum Schleswig-Holstein Mitte)
Wallace, Chris (Cambridge Institute of Public Health)
Smith, Kenneth G. C. (Jeffrey Cheah Biomedical Centre University of Cambridge)
Universitat Autònoma de Barcelona

Date:	2019
Abstract:	Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.
Grants:	Ministerio de Economía y Competitividad SAF 2017-88275-R Instituto de Salud Carlos III PI 18/00461
Rights:	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.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Antibodies, Antineutrophil Cytoplasmic ; Eosinophils ; Genetic Association Studies ; Genetic Loci ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Granulomatosis with Polyangiitis ; Humans ; Mendelian Randomization Analysis
Published in:	Nature communications, Vol. 10 Núm. 1 (january 2019) , p. 5120, ISSN 2041-1723

DOI: 10.1038/s41467-019-12515-9
PMID: 31719529

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