Publikation
Genetically distinct clinical subsets, and associations with asthma and eosinophil abundance, within Eosinophilic Granulomatosis with Polyangiitis
Wissenschaftlicher Artikel/Review - 10.12.2018
Neumann Thomas, Martorana Davide, Moosig Frank, Ohlsson Sophie, Quickert Stefanie, Ramirez Stefanie, Rewerska Barbara, Schett Georg, Sinico Renato A., Szczeklik Wojciech, Tesar Vladimir, Vukcevic Damjan, Terrier Benjamin, Watts Richard A, Vaglio Augusto, Holle Julia U, Wallace Chris, Little Mark A., Leslie Stephen, Lamprecht Peter, Lyons Paul A, Peters James E, Alberici Frederica, Liley James E, Coulson Richard M.R., Astle William, Baldini Chiara, Francesco Bonatti, Cid María C, Elding Heather, Emmi Giacomo, Epplen Jörg, Guillevin Loic, Jayne David R.W., Jiang Tao, Gunnarsson Iva, Smith Kenneth G.C.
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Eosinophilic granulomatosis with polyangiitis (EGPA: formerly Churg-Strauss syndrome) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasm antibodies (ANCA) specific for myeloperoxidase (MPO). We performed a genome-wide association study (GWAS) of EGPA, testing 7.5 million genetic variants in 684 cases and 6,838 controls. Case-control analyses were performed for EGPA as a whole, and stratified by ANCA. To increase power, we used a conditional false discovery rate method to leverage findings from GWASs of related phenotypes. In total, 11 variants were associated with EGPA, two specifically with ANCA-negative EGPA, and one (HLA-DQ) with MPO+ANCA EGPA. Many variants were associated with asthma, eosinophilic and immune-mediated diseases and, strikingly, nine were associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia underlies EGPA susceptibility. We demonstrate that EGPA comprises two genetically and clinically distinct syndromes, with ANCA-negative EGPA genetically more similar to asthma. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an MHC association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Five identified candidate genes are targets of therapies in development, supporting their exploration in EGPA.