Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status
journal contributionposted on 14.05.2020, 07:58 by Paul A Lyons, James E Peters, Federico Alberici, James Liley, Richard MR Coulson, William Astle, Chiara Baldini, Francesco Bonatti, Maria C Cid, Heather Elding, Giacomo Emmi, Joerg Epplen, Loic Guillevin, David RW 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, Mohammed Akil, Jonathan Barratt, Neil Basu, Adam S Butterworth, Ian Bruce, Michael Clarkson, Niall Conlon, Bhaskar DasGupta, Timothy WR Doulton, Georgina Espigol-Frigole, Oliver Flossmann, Armando Gabrielli, Jolanta Gasior, Gina Gregorini, Giuseppe Guida, Jose Hernandez-Rodriguez, Zdenka Hruskova, Amy Hudson, Ann Knight, Peter Lanyon, Raashid Luqmani, Malgorzata Magliano, Angelo A Manfredi, Christopher Marguerie, Federica Maritati, Chiara Marvisi, Neil J McHugh, Eamonn Molloy, Allan Motyer, Chetan Mukhtyar, Leonid Padyukov, Alberto Pesci, Sergio Prieto-Gonzalez, Marc Ramentol-Sintas, Petra Reis, Dario Roccatello, Patrizia Rovere-Querini, Carlo Salvarani, Francesca Santarsia, Roser Solans-Laque, Nicole Soranzo, Jo Taylor, Julie Wessels, Jochen Zwerina, Benjamin Terrier, Richard A Watts, Augusto Vaglio, Julia U Holle, Chris Wallace, Kenneth GC Smith
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.