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

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posted on 14.05.2020, 07:58 by Paul A Lyons, James E Peters, Federico Alberici, James Liley, Richard MR Coulson, William Astle, Chiara Baldini, Francesco Bonatti, Maria C Cid, Heather Elding, Giacomo Emmi, Joerg Epplen, Loic Guillevin, David RW 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, Mohammed Akil, Jonathan Barratt, Neil Basu, Adam S Butterworth, Ian Bruce, Michael Clarkson, Niall Conlon, Bhaskar DasGupta, Timothy WR Doulton, Georgina Espigol-Frigole, Oliver Flossmann, Armando Gabrielli, Jolanta Gasior, Gina Gregorini, Giuseppe Guida, Jose Hernandez-Rodriguez, Zdenka Hruskova, Amy Hudson, Ann Knight, Peter Lanyon, Raashid Luqmani, Malgorzata Magliano, Angelo A Manfredi, Christopher Marguerie, Federica Maritati, Chiara Marvisi, Neil J McHugh, Eamonn Molloy, Allan Motyer, Chetan Mukhtyar, Leonid Padyukov, Alberto Pesci, Sergio Prieto-Gonzalez, Marc Ramentol-Sintas, Petra Reis, Dario Roccatello, Patrizia Rovere-Querini, Carlo Salvarani, Francesca Santarsia, Roser Solans-Laque, Nicole Soranzo, Jo Taylor, Julie Wessels, Jochen Zwerina, Benjamin Terrier, Richard A Watts, Augusto Vaglio, Julia U Holle, Chris Wallace, Kenneth GC Smith
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.

Funding

This work was funded primarily by Project Grants from Arthritis Research UK (20593 to Drs. Smith and Lyons) and the British Heart Foundation (PG/13/64/30435 to Drs. Smith and Lyons). Additional support was provided by the NIHR Cambridge Biomedical Research Centre, the West Anglia Comprehensive Research Network, a Medical Research Council Programme Grant (MR/L019027/1 to Dr. Smith), a Wellcome Trust Investigator Award (200871/Z/16/Z to Dr. Smith), a NIHR Senior Investigator Award (to Dr. Smith), a Wellcome Trust Senior Research Fellowship (WT107881 to Dr. Wallace), a Medical Research Council grant (MC_UU_00002/4 to Dr. Wallace), a Wellcome Trust Mathematical Genomics and Medicine Programme Studentship (to Dr. Liley), a Career Development Award from the Cambridge British Heart Foundation Centre for Research Excellence and a UK Research Innovation Fellowship (RE/13/6/30180 and MR/S004068/1 to Dr. Peters). Additional aspects of this work were supported by the following funding: a Science Foundation Ireland Grant (11/Y/B2093 to Dr Little); an Australian National Health and Medical Research Council (NH&MRC), Career Development Fellowship (ID 1053756) and a Victorian Life Sciences Computation Initiative (VLSCI) grant number (VR0240) on its Peak Computing Facility at the University of Melbourne, an initiative of the Victorian Government, Australia (to Dr Leslie); Research at the Murdoch Children’s Research Institute was supported by the Victorian Government’s Operational Infrastructure Support Program; Project RVO 64 165 of the Ministry of Health of Czech Republic (to Dr Tesar); Ministerio de Economía y Competitividad (SAF SAF 2017-88275-R), FEDER una manera de hacer Europa) and CERCA programme (to Drs Cid and Hernández-Rodríguez) and Instituto de Salud Carlos III (PI 18/00461) (to Drs Espígol-Frigolé and Prieto-Gonzalez); Prof Bruce is an NIHR Senior Investigator and is supported by Versus Arthritis, the National Institute for Health Research Manchester Biomedical

History

Citation

Nature Communications (2019) 10:5120

Author affiliation

Department of Respiratory Sciences

Version

VoR (Version of Record)

Published in

Nature Communications

Volume

10

Issue

1

Publisher

Nature Research

eissn

2041-1723

Acceptance date

01/07/2019

Copyright date

2019

Publisher version

https://www.nature.com/articles/s41467-019-12515-9#Abs1

Language

English