Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status.

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.

• Authors: Paul A Lyons, James E Peters, Federico Alberici, James Liley, Richard M R Coulson, William Astle, Chiara Baldini, Francesco Bonatti, Maria C Cid, Heather Elding, Giacomo Emmi, Jörg Epplen, Loïc Guillevin, David R W Jayne, Tao Jiang, Iva Gunnarsson, Peter Lamprecht, Stephen Leslie, Mark A Little, Davide Martorana, Frank Moosig, Thomas Neumann, Sophie Ohlsson, Stefanie Quickert, Giuseppe A Ramirez, Barbara Rewerska, Georg Schett, Renato A Sinico, Wojciech Szczeklik, Vladimir Tesar, Damjan Vukcevic, European Vasculitis Genetics Consortium, Benjamin Terrier, Richard A Watts, Augusto Vaglio, Julia U Holle, Chris Wallace, Kenneth G C Smith
• Journal: Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 5120 (11 12 2019) ISSN: 2041-1723 [Electronic] England
• PMID: 31719529 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Antineutrophil Cytoplasmic

Topics

• Antibodies, Antineutrophil Cytoplasmic (metabolism)
• Eosinophils (pathology)
• Genetic Association Studies
• Genetic Loci
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Granulomatosis with Polyangiitis (genetics, immunology)
• Humans
• Mendelian Randomization Analysis