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

Publication

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

Journal Paper/Review - Nov 12, 2019

Lyons Paul A, Moosig Frank, Neumann Thomas, Ohlsson Sophie, Quickert Stefanie, Ramirez Giuseppe A, Rewerska Barbara, Schett Georg, Sinico Renato A, Szczeklik Wojciech, Tesar Vladimir, Vukcevic Damjan, European Vasculitis Genetics Consortium, Terrier Benjamin, Watts Richard A, Vaglio Augusto, Holle Julia U, Wallace Chris, Martorana Davide, Little Mark A, Peters James E, Alberici Federico, Liley James, Coulson Richard M R, Astle William, Baldini Chiara, Francesco Bonatti, Cid María C, Elding Heather, Emmi Giacomo, Epplen Jörg, Guillevin Loic, Jayne David R W, Jiang Tao, Gunnarsson Iva, Lamprecht Peter, Leslie Stephen, Smith Kenneth G C

Citation

Lyons P, Moosig F, Neumann T, Ohlsson S, Quickert S, Ramirez G, Rewerska B, Schett G, Sinico R, Szczeklik W, Tesar V, Vukcevic D, European Vasculitis Genetics Consortium, Terrier B, Watts R, Vaglio A, Holle J, Wallace C, Martorana D, Little M, Peters J, Alberici F, Liley J, Coulson R, Astle W, Baldini C, Francesco B, Cid M, Elding H, Emmi G, Epplen J, Guillevin L, Jayne D, Jiang T, Gunnarsson I, Lamprecht P, Leslie S, Smith K. Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status. Nat Commun 2019; 10:5120.

Type

Journal Paper/Review (English)

Journal

Nat Commun 2019; 10

Publication Date

Nov 12, 2019

Issn Electronic

2041-1723

Pages

5120

Brief description/objective

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.