Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-12515-9
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Funding
- Arthritis Research UK [20593]
- British Heart Foundation [PG/13/64/30435]
- NIHR Cambridge Biomedical Research Centre
- Medical Research Council Programme Grant [MR/L019027/1]
- Wellcome Trust [200871/Z/16/Z, WT107881]
- NIHR
- Medical Research Council [MC_UU_00002/4]
- Wellcome Trust Mathematical Genomics and Medicine Programme Studentship
- Cambridge British Heart Foundation Centre for Research Excellence
- UK Research Innovation Fellowship [RE/13/6/30180, MR/S004068/1]
- Science Foundation Ireland [11/Y/B2093]
- Australian National Health and Medical Research Council (NHMRC)
- Career Development Fellowship [1053756]
- Victorian Life Sciences Computation Initiative (VLSCI) on its Peak Computing Facility at the University of Melbourne, an initiative of the Victorian Government, Australia [VR0240]
- Victorian Government's Operational Infrastructure Support Program
- Ministry of Health of Czech Republic [RVO 64 165]
- Ministerio de Economia y Competitividad [SAF SAF 2017-88275-R]
- FEDER una manera de hacer Europa
- CERCA programme
- Instituto de Salud Carlos III [PI 18/00461]
- Versus Arthritis
- National Institute for Health Research Manchester Biomedical Research Centre
- NIHR Manchester Clinical Research Facility
- West Anglia Comprehensive Research Network
- MRC [MR/S004068/1, MR/S004068/2, MC_UU_00002/4] Funding Source: UKRI
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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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