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

Lyons, P. A. et al. (2019) Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status. Nature Communications, 10, 5120. (doi: 10.1038/s41467-019-12515-9) (PMID:31719529) (PMCID:PMC6851141)

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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.

Item Type:Articles
Additional Information: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 funded by Arthritis Research UK, the National Institute for Health Research Manchester Biomedical Research Unit and the NIHR/Wellcome Trust Manchester Clinical Research Facility.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Basu, Professor Neil
Authors: Lyons, P. A., Peters, J. E., Alberici, F., Liley, J., Coulson, R. M.R., Astle, W., Baldini, C., Bonatti, F., Cid, M. C., Elding, H., Emmi, G., Epplen, J., Guillevin, L., Jayne, D. R.W., Jiang, T., Gunnarsson, I., Lamprecht, P., Leslie, S., Little, M. A., Martorana, D., Moosig, F., Neumann, T., Ohlsson, S., Quickert, S., Ramirez, G., Rewerska, B., Schett, G., Sinico, R. A., Szczeklik, W., Tesar, V., Vukcevic, D., The European Vasculitis Genetics Consortium, , Terrier, B., Watts, R. A., Vaglio, A., Holle, J. U., Wallace, C., and Smith, K. G.C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Nature Communications
Publisher:Nature Publishing Group
ISSN:2041-1723
ISSN (Online):2041-1723
Published Online:12 November 2019
Copyright Holders:Copyright © The Authors 2019
First Published:First published in Nature Communications 10:5120
Publisher Policy:Reproduced under a Creative Commons License

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