Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status
(2019) In Nature Communications 10.- 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... (More)
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.
(Less)
- author
- author collaboration
- organization
- publishing date
- 2019-11-12
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Nature Communications
- volume
- 10
- article number
- 5120
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:85074947375
- pmid:31719529
- ISSN
- 2041-1723
- DOI
- 10.1038/s41467-019-12515-9
- language
- English
- LU publication?
- yes
- id
- 7f7c7382-1909-4922-b0ae-c373d135efd0
- date added to LUP
- 2019-11-18 10:20:38
- date last changed
- 2024-09-19 13:00:21
@article{7f7c7382-1909-4922-b0ae-c373d135efd0, abstract = {{<p>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.</p>}}, author = {{Lyons, Paul A and Peters, James E and Alberici, Federico and Liley, James and Coulson, Richard M R and Astle, William and Baldini, Chiara and Bonatti, Francesco and Cid, Maria C and Elding, Heather and Emmi, Giacomo and Epplen, Jörg and Guillevin, Loïc and Jayne, David R W and Jiang, Tao and Gunnarsson, Iva and Lamprecht, Peter and Leslie, Stephen and Little, Mark A and Martorana, Davide and Moosig, Frank and Neumann, Thomas and Ohlsson, Sophie and Quickert, Stefanie and Ramirez, Giuseppe A and Rewerska, Barbara and Schett, Georg and Sinico, Renato A and Szczeklik, Wojciech and Tesar, Vladimir and Vukcevic, Damjan and Terrier, Benjamin and Watts, Richard A and Vaglio, Augusto and Holle, Julia U and Wallace, Chris and Smith, Kenneth G C}}, issn = {{2041-1723}}, language = {{eng}}, month = {{11}}, publisher = {{Nature Publishing Group}}, series = {{Nature Communications}}, title = {{Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status}}, url = {{http://dx.doi.org/10.1038/s41467-019-12515-9}}, doi = {{10.1038/s41467-019-12515-9}}, volume = {{10}}, year = {{2019}}, }