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

2019; Nature Portfolio; Volume: 10; Issue: 1 Linguagem: Inglês

10.1038/s41467-019-12515-9

2041-1723

Paul Lyons, James E. Peters, Federico Alberici, James Liley, Richard Coulson, William J. Astle, Chiara Baldini, Francesco Bonatti, María C. Cid, Heather Elding, Giacomo Emmi, Jörg T. Epplen, Loı̈c Guillevin, David 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 Alberto Sinico, Wojciech Szczeklik, Vladimı́r Tesař, Damjan Vukcevic, Mohammed Akil, Jonathan Barratt, Neil Basu, Adam S. Butterworth, Ian N Bruce, Michael Clarkson, Niall Conlon, Bhaskar Dasgupta, Timothy Doulton, Georgina Espígol‐Frigolé, Oliver Floßmann, Tianlu Li, Jolanta Gąsior, Gina Gregorini, Giuseppe Guida, José Hernández‐Rodríguez, Zdenka Hrušková, Amy W. Hudson, Ann Knight, Peter Lanyon, Raashid Luqmani, Malgorzata Magliano, Angelo A. Manfredi, Christopher Marguerie, Federica Maritati, Chiara Marvisi, Neil McHugh, Eamonn Molloy, Allan Motyer, Chetan Mukhtyar, Leonid Padyukov, Alberto Pesci, Sergio Prieto‐González, Marc Ramentol-Sintas, Petra Reis, Dario Roccatello, Patrizia Rovere‐Querini, Carlo Salvarani, Francesca Santarsia, Roser Soláns-Laqué, Nicole Soranzo, Jo Taylor, Julie Wessels, Jochen Zwerina, Benjamin Terrier, Richard A. Watts, Augusto Vaglio, Julia U. Holle, Chris Wallace, Kenneth G. C. Smith,

Mast cells and histamine

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.