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Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status
PA. Lyons, JE. Peters, F. Alberici, J. Liley, RMR. Coulson, W. Astle, C. Baldini, F. Bonatti, MC. Cid, H. Elding, G. Emmi, J. Epplen, L. Guillevin, DRW. Jayne, T. Jiang, I. Gunnarsson, P. Lamprecht, S. Leslie, MA. Little, D. Martorana, F. Moosig,...
Jazyk angličtina Země Velká Británie
Typ dokumentu časopisecké články, práce podpořená grantem
Grantová podpora
MC_UU_00002/4
Medical Research Council - United Kingdom
MR/S004068/1
Medical Research Council - United Kingdom
RG/13/13/30194
British Heart Foundation - United Kingdom
RG/18/13/33946
British Heart Foundation - United Kingdom
Free Medical Journals od 2010
Nature Open Access od 2010-12-01
PubMed Central od 2012
Europe PubMed Central od 2012
ProQuest Central od 2010-01-01
Open Access Digital Library od 2015-01-01
Open Access Digital Library od 2015-01-01
Medline Complete (EBSCOhost) od 2012-11-01
Health & Medicine (ProQuest) od 2010-01-01
ROAD: Directory of Open Access Scholarly Resources od 2010
Odkazy
PubMed
31719529
DOI
10.1038/s41467-019-12515-9
Knihovny.cz E-zdroje
- MeSH
- celogenomová asociační studie * MeSH
- eozinofily patologie MeSH
- genetická predispozice k nemoci * MeSH
- genetické asociační studie MeSH
- genetické lokusy * MeSH
- granulomatóza s polyangiitidou genetika imunologie MeSH
- lidé MeSH
- mendelovská randomizace MeSH
- protilátky proti cytoplazmě neutrofilů metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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.
Department of Experimental and Clinical Medicine University of Firenze Firenze Italy
Department of Nephrology Division of Clinical Sciences Lund University Lund Sweden
Department of Rheumatology and Clinical Immunology University of Lübeck 23562 Lübeck Germany
Human Genetics Ruhr University Bochum Bochum Germany
Jagiellonian University Medical College Kraków Poland
Rheumatology Unit University of Pisa Pisa Italy
Rheumazentrum Schleswig Holstein Mitte Neumünster Germany
Service de Médecine Interne Hôpital Cochin 75679 Paris Cedex 14 France
Unit of Molecular Genetics University Hospital of Parma Via Gramsci 14 43126 Parma Italy
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- $a Lyons, Paul A $u Department of Medicine, University of Cambridge School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK. Cambridge Institute for Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre University of Cambridge, Cambridge, CB2 0AW, UK.
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- $a 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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