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

Lyons, Paul A ; Peters, James E ; Alberici, Federico ; Liley, James ; Coulson, Richard M R ; Astle, William ; Baldini, Chiara ; Bonatti, Francesco ; Cid, Maria C and Elding, Heather , et al. (2019) In Nature Communications 10.
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... (More)

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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published
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Nature Communications
volume
10
article number
5120
publisher
Nature Publishing Group
external identifiers
  • scopus:85074947375
  • pmid:31719529
ISSN
2041-1723
DOI
10.1038/s41467-019-12515-9
language
English
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yes
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7f7c7382-1909-4922-b0ae-c373d135efd0
date added to LUP
2019-11-18 10:20:38
date last changed
2020-10-27 02:30:33
@article{7f7c7382-1909-4922-b0ae-c373d135efd0,
  abstract     = {<p>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.</p>},
  author       = {Lyons, Paul A and Peters, James E and Alberici, Federico and Liley, James and Coulson, Richard M R and Astle, William and Baldini, Chiara and Bonatti, Francesco and Cid, Maria C and Elding, Heather and Emmi, Giacomo and Epplen, Jörg and Guillevin, Loïc and Jayne, David R W and Jiang, Tao and Gunnarsson, Iva and Lamprecht, Peter and Leslie, Stephen and Little, Mark A and Martorana, Davide and Moosig, Frank and Neumann, Thomas and Ohlsson, Sophie and Quickert, Stefanie and Ramirez, Giuseppe A and Rewerska, Barbara and Schett, Georg and Sinico, Renato A and Szczeklik, Wojciech and Tesar, Vladimir and Vukcevic, Damjan and Terrier, Benjamin and Watts, Richard A and Vaglio, Augusto and Holle, Julia U and Wallace, Chris and Smith, Kenneth G C},
  issn         = {2041-1723},
  language     = {eng},
  month        = {11},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status},
  url          = {http://dx.doi.org/10.1038/s41467-019-12515-9},
  doi          = {10.1038/s41467-019-12515-9},
  volume       = {10},
  year         = {2019},
}