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

The European Vasculitis Genetics Consortium

doi:10.1038/s41467-019-12515-9

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

The European Vasculitis Genetics Consortium

Research output: Contribution to journal › Article › peer-review

201 Citations (SciVal)

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.

Original language	English
Article number	5120
Journal	Nature Communications
Volume	10
Issue number	1
Early online date	12 Nov 2019
DOIs	https://doi.org/10.1038/s41467-019-12515-9
Publication status	Published - 1 Dec 2019

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 Research Centre and the NIHR Manchester Clinical Research Facility. We thank the Centre for Integrated Genomic Medical Research Biobank for sample storage and preparation, and AROS Applied Biotechnology (Aarhus, Denmark) and Cambridge Genomic Services (Cambridge, UK) for genotyping.

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-019-12515-9Licence: CC BY

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title = "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.",

author = "{The European Vasculitis Genetics Consortium} and Lyons, {Paul A.} and Peters, {James E.} and Federico Alberici and James Liley and Coulson, {Richard M.R.} and William Astle and Chiara Baldini and Francesco Bonatti and Cid, {Maria C.} and Heather Elding and Giacomo Emmi and J{\"o}rg Epplen and Lo{\"i}c Guillevin and Jayne, {David R.W.} and Tao Jiang and Iva Gunnarsson and Peter Lamprecht and Stephen Leslie and Little, {Mark A.} and Davide Martorana and Frank Moosig and Thomas Neumann and Sophie Ohlsson and Stefanie Quickert and Ramirez, {Giuseppe A.} and Barbara Rewerska and Georg Schett and Sinico, {Renato A.} and Wojciech Szczeklik and Vladimir Tesar and Damjan Vukcevic and Mohammed Akil and Jonathan Barratt and Neil Basu and Butterworth, {Adam S.} and Ian Bruce and Michael Clarkson and Niall Conlon and Bhaskar DasGupta and Doulton, {Timothy W.R.} and Georgina Esp{\'i}gol-Frigol{\'e} and Oliver Flossmann and Armando Gabrielli and Jolanta Gasior and Gina Gregorini and Giuseppe Guida and Jos{\'e} Hern{\'a}ndez-Rodr{\'i}guez and Zdenka Hruskova and Amy Hudson and McHugh, {Neil J.}",

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AU - Peters, James E.

AU - Alberici, Federico

AU - Liley, James

AU - Coulson, Richard M.R.

AU - Astle, William

AU - Baldini, Chiara

AU - Bonatti, Francesco

AU - Cid, Maria C.

AU - Elding, Heather

AU - Emmi, Giacomo

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AU - Guillevin, Loïc

AU - Jayne, David R.W.

AU - Jiang, Tao

AU - Gunnarsson, Iva

AU - Lamprecht, Peter

AU - Leslie, Stephen

AU - Little, Mark A.

AU - Martorana, Davide

AU - Moosig, Frank

AU - Neumann, Thomas

AU - Ohlsson, Sophie

AU - Quickert, Stefanie

AU - Ramirez, Giuseppe A.

AU - Rewerska, Barbara

AU - Schett, Georg

AU - Sinico, Renato A.

AU - Szczeklik, Wojciech

AU - Tesar, Vladimir

AU - Vukcevic, Damjan

AU - Akil, Mohammed

AU - Barratt, Jonathan

AU - Basu, Neil

AU - Butterworth, Adam S.

AU - Bruce, Ian

AU - Clarkson, Michael

AU - Conlon, Niall

AU - DasGupta, Bhaskar

AU - Doulton, Timothy W.R.

AU - Espígol-Frigolé, Georgina

AU - Flossmann, Oliver

AU - Gabrielli, Armando

AU - Gasior, Jolanta

AU - Gregorini, Gina

AU - Guida, Giuseppe

AU - Hernández-Rodríguez, José

AU - Hruskova, Zdenka

AU - Hudson, Amy

AU - McHugh, Neil J.

PY - 2019/12/1

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N2 - 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.

AB - 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.

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

Abstract

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