Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status.
Accepted version
Peer-reviewed
Repository URI
Repository DOI
Change log
Authors
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.
Description
Keywords
Journal Title
Conference Name
Journal ISSN
2041-1723
Volume Title
Publisher
Publisher DOI
Rights
Sponsorship
British Heart Foundation (None)
ARTHRITIS RESEARCH UK (20593)
Wellcome Trust (200871/Z/16/Z)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0515-10015)
Wellcome Trust (107881/Z/15/Z)
MRC (1185)
Medical Research Council (MR/S004068/1)
Medical Research Council (MC_UU_00002/4)
British Heart Foundation (None)
British Heart Foundation (None)
British Heart Foundation (RG/18/13/33946)