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

PA Lyons, JE Peters, F Alberici, J Liley, RMR Coulson, W Astle, C Baldini, F Bonatti, MC Cid, H Elding, G Emmi, J Epplen, L Guillevin, DRW Jayne, T Jiang, I Gunnarsson, P Lamprecht, S Leslie, MA Little, D MartoranaF Moosig, T Neumann, S Ohlsson, S Quickert, GA Ramirez, B Rewerska, G Schett, RA Sinico, W Szczeklik, V Tesar, D Vukcevic, M Akil, J Barratt, N Basu, AS Butterworth, I Bruce, M Clarkson, N Conlon, B DasGupta, TWR Doulton, G Espígol-Frigolé, O Flossmann, A Gabrielli, J Gasior, G Gregorini, G Guida, J Hernández-Rodríguez, Z Hruskova, A Hudson, A Knight, P Lanyon, R Luqmani, M Magliano, AA Manfredi, C Marguerie, F Maritati, C Marvisi, NJ McHugh, E Molloy, A Motyer, C Mukhtyar, L Padyukov, A Pesci, S Prieto-Gonzalez, M Ramentol-Sintas, P Reis, D Roccatello, P Rovere-Querini, C Salvarani, F Santarsia, R Solans-Laque, N Soranzo, J Taylor, J Wessels, J Zwerina, B Terrier, RA Watts, A Vaglio, JU Holle, C Wallace, KGC Smith, The European Vasculitis Genetics Consortium

Research output: Contribution to journalArticlepeer-review

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. © 2019, The Author(s).
Original languageEnglish
JournalNat. Commun.
Volume10
DOIs
Publication statusPublished - 2019

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