Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status

Paul A Lyons, James E Peters, Federico Alberici, James Liley, Richard M. R. Coulson, William Astle, Chiara Baldini, Francesco Bonatti, Maria C Cid, Heather Elding, Giacomo Emmi, Jörg Epplen, Loïc Guillevin, David R. W. Jayne, Tao Jiang, Iva Gunnarsson, Peter Lamprecht, Stephen Leslie, Mark A. Little, Davide Martorana, Frank Moosig, Thomas Neumann, Sophie Ohlsson, Stefanie Quickert, Giuseppe A. Ramirez, Barbara Rewerska, Georg Schett, Renato A. Sinico, Wojciech Szczeklik, Vladimir Tesar, Damjan Vukcevic, Benjamin Terrier, Richard A Watts, Augusto Vaglio, Julia U Holle, Chris Wallace and Kenneth G. C. Smith ()
Additional contact information
Paul A Lyons: University of Cambridge
James E Peters: University of Cambridge
Federico Alberici: University of Cambridge
James Liley: University of Cambridge
Richard M. R. Coulson: University of Cambridge
William Astle: University of Cambridge, Strangeways Research Laboratory, Wort’s Causeway
Chiara Baldini: University of Pisa
Francesco Bonatti: University Hospital of Parma
Maria C Cid: University of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CRB-CELLEX
Heather Elding: University of Cambridge, Strangeways Research Laboratory, Wort’s Causeway
Giacomo Emmi: University of Firenze
Jörg Epplen: Ruhr University Bochum
Loïc Guillevin: Service de Médecine Interne, Hôpital Cochin
David R. W. Jayne: University of Cambridge
Tao Jiang: University of Cambridge, Strangeways Research Laboratory, Wort’s Causeway
Iva Gunnarsson: Karolinska University Hospital, Karolinska Institute
Peter Lamprecht: University of Lübeck
Stephen Leslie: University of Melbourne
Mark A. Little: Tallaght Hospital
Davide Martorana: University Hospital of Parma
Frank Moosig: Rheumazentrum Schleswig-Holstein Mitte
Thomas Neumann: Jena University Hospital
Sophie Ohlsson: Lund University
Stefanie Quickert: Jena University Hospital
Giuseppe A. Ramirez: Università Vita Salute San Raffaele and IRCCS Ospedale San Raffaele
Barbara Rewerska: Jagiellonian University Medical College
Georg Schett: Rheumatology and Immunology, Friedrich Alexander University Erlangen-Nuremberg and Universitatsklinikum Erlangen
Renato A. Sinico: Università degli Studi di Milano–Bicocca (School of Medicine and Surgery)
Wojciech Szczeklik: Jagiellonian University Medical College
Vladimir Tesar: 1st Faculty of Medicine and General University Hospital, Charles University
Damjan Vukcevic: University of Melbourne
Benjamin Terrier: Service de Médecine Interne, Hôpital Cochin
Richard A Watts: Ipswich Hospital
Augusto Vaglio: University of Firenze, and Meyer Children’s Hospital
Julia U Holle: Rheumazentrum Schleswig-Holstein Mitte
Chris Wallace: University of Cambridge
Kenneth G. C. Smith: University of Cambridge

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12515-9

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