• 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, Jayne David R W DRW Department of Medicine, University of Cambridge School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0QQ,, 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, European Vasculitis Genetics Consortium, Benjamin Terrier, Richard A Watts, Augusto Vaglio, Julia U Holle, Chris Wallace, and Smith Kenneth G C KGC Department of Medicine, University of Cambridge School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0Q.
• Department of Medicine, University of Cambridge School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
• Nat Commun. 2019 Nov 12; 10 (1): 5120.

AbstractEosinophilic 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.

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