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.
Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status / Lyons, P. A.; Peters, J. E.; Alberici, F.; Liley, J.; Coulson, R. M. R.; Astle, W.; Baldini, C.; Bonatti, F.; Cid, M. C.; Elding, H.; Emmi, G.; Epplen, J.; Guillevin, L.; Jayne, D. R. W.; Jiang, T.; Gunnarsson, I.; Lamprecht, P.; Leslie, S.; Little, M. A.; Martorana, D.; Moosig, F.; Neumann, T.; Ohlsson, S.; Quickert, S.; Ramirez, G. A.; Rewerska, B.; Schett, G.; Sinico, R. A.; Szczeklik, W.; Tesar, V.; Vukcevic, D.; Akil, M.; Barratt, J.; Basu, N.; Butterworth, A. S.; Bruce, I.; Clarkson, M.; Conlon, N.; Dasgupta, B.; Doulton, T. W. R.; Espigol-Frigole, G.; Flossmann, O.; Gabrielli, A.; Gasior, J.; Gregorini, G.; Guida, G.; Hernandez-Rodriguez, J.; Hruskova, Z.; Hudson, A.; Knight, A.; Lanyon, P.; Luqmani, R.; Magliano, M.; Manfredi, A. A.; Marguerie, C.; Maritati, F.; Marvisi, C.; Mchugh, N. J.; Molloy, E.; Motyer, A.; Mukhtyar, C.; Padyukov, L.; Pesci, A.; Prieto-Gonzalez, S.; Ramentol-Sintas, M.; Reis, P.; Roccatello, D.; Rovere-Querini, P.; Salvarani, C.; Santarsia, F.; Solans-Laque, R.; Soranzo, N.; Taylor, J.; Wessels, J.; Zwerina, J.; Terrier, B.; Watts, R. A.; Vaglio, A.; Holle, J. U.; Wallace, C.; Smith, K. G. C.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 10:1(2019), pp. 5120-5120. [10.1038/s41467-019-12515-9]
Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status
Marvisi C.;Salvarani C.;
2019
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.
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