Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status
Open Access
- 12 November 2019
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 10 (1), 5120
- https://doi.org/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.This publication has 53 references indexed in Scilit:
- Improved Detection of Common Variants Associated with Schizophrenia and Bipolar Disorder Using Pleiotropy-Informed Conditional False Discovery RatePLoS Genetics, 2013
- Antineutrophil cytoplasmic antibody-associated vasculitides: is it time to split up the group?Annals Of The Rheumatic Diseases, 2013
- Bayesian refinement of association signals for 14 loci in 3 common diseasesNature Genetics, 2012
- A Large-Scale, Consortium-Based Genomewide Association Study of AsthmaThe New England Journal of Medicine, 2010
- The BH3-Mimetic ABT-737 Induces Mast Cell Apoptosis In Vitro and In Vivo: Potential for TherapeuticsThe Journal of Immunology, 2010
- BH3 mimetics antagonizing restricted prosurvival Bcl-2 proteins represent another class of selective immune modulatory drugsProceedings of the National Academy of Sciences of the United States of America, 2010
- A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association StudiesPLoS Genetics, 2009
- GATA3 and the T-cell lineage: essential functions before and after T-helper-2-cell differentiationNature Reviews Immunology, 2009
- Associations of Churg‐Strauss syndrome with the HLA–DRB1 locus, and relationship to the genetics of antineutrophil cytoplasmic antibody–associated vasculitides: Comment on the article by Vaglio et alArthritis & Rheumatism, 2007
- HLA–DRB4 as a genetic risk factor for Churg‐Strauss syndromeArthritis & Rheumatism, 2007