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

Lyons PA, Peters JE, Alberici F, Liley J, Coulson RM, Astle W, Baldini C, Bonatti F, Cid MC, Elding H, Emmi G, Epplen J, Guillevin L, Jayne DR, Jiang T, Gunnarsson I, Lamprecht P, Leslie S, Little MA, Martorana D, Moosig F, Neumann T, Ohlsson S, Quickert S, Ramirez GA, Rewerska B, Schett G, Sinico RA, Szczeklik W, Tesar V, Vukcevic D, Terrier B, Watts RA, Vaglio A, Holle JU, Wallace C, Smith KG (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Book Volume: 10

Pages Range: 5120-

Journal Issue: 1

DOI: 10.1038/s41467-019-12515-9

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 with CRIS profile

Involved external institutions

School of Clinical Medicine United Kingdom (GB) Strangeways Research Laboratory United Kingdom (GB) University of Pisa / Università di Pisa (UniPi) Italy (IT) University of Parma / Università degli Studi di Parma Italy (IT) Universitat de Barcelona (UB) / University of Barcelona Spain (ES) Università degli Studi di Firenze / University of Florence Italy (IT) Ruhr-Universität Bochum (RUB) Germany (DE) Hôpital Cochin France (FR) Karolinska University Hospital / Karolinska Universitetssjukhuset Sweden (SE) Universität zu Lübeck Germany (DE) The University of Melbourne Australia (AU) Trinity College Dublin Ireland (IE) Rheumazentrum Schleswig-Holstein Mitte Germany (DE) Lund University / Lunds universitet Sweden (SE) Universitätsklinikum Jena Germany (DE) Università Vita-Salute San Raffaele (UniSR) Italy (IT) Jagiellonian University / Uniwersytet Jagielloński (UJ) Poland (PL) University of Milano-Bicocca / Università degli Studi di Milano-Bicocca, UNIMIB Italy (IT) Ipswich Hospital United Kingdom (GB) Azienda Ospedaliera Universitaria Meyer Italy (IT) Univerzita Karlova v Praze / Charles University in Prague Czech Republic (CZ)

How to cite

APA:

Lyons, P.A., Peters, J.E., Alberici, F., Liley, J., Coulson, R.M., Astle, W.,... Smith, K.G. (2019). Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status. Nature Communications, 10(1), 5120-. https://doi.org/10.1038/s41467-019-12515-9

MLA:

Lyons, Paul A., et al. "Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status." Nature Communications 10.1 (2019): 5120-.

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