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Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status
Univ Cambridge, Sch Clin Med, Dept Med, Cambridge Biomed Campus, Cambridge CB2 0QQ, England;Univ Cambridge, Jeffrey Cheah Biomed Ctr, Cambridge Inst Therapeut Immunol & Infect Dis, Cambridge CB2 0AW, England.
Univ Cambridge, Sch Clin Med, Dept Med, Cambridge Biomed Campus, Cambridge CB2 0QQ, England;Univ Cambridge, Dept Publ Hlth & Primary Care, BHF Cardiovasc Epidemiol Unit, Strangeways Res Lab, Worts Causeway, Cambridge CB1 8RN, England;Hlth Data Res UK, Cambridge, England.
Univ Cambridge, Sch Clin Med, Dept Med, Cambridge Biomed Campus, Cambridge CB2 0QQ, England;San Carlo Borromeo Hosp, Nephrol & Immunopathol Unit, ASST Santi Paolo & Carlo, Milan, Italy;Univ Milan, Dipartimento Sci Salute, Milan, Italy.ORCID iD: 0000-0002-1686-5709
Univ Cambridge, Sch Clin Med, Dept Med, Cambridge Biomed Campus, Cambridge CB2 0QQ, England;Cambridge Inst Publ Hlth, Med Res Council Biostat Unit, Cambridge Biomed Campus,Forvie Site,Robinson Way, Cambridge CB2 0SR, England.
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2019 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 5120Article in journal (Refereed) Published
Abstract [en]

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.
Place, publisher, year, edition, pages
2019. Vol. 10, article id 5120
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Rheumatology and Autoimmunity
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URN: urn:nbn:se:uu:diva-398078DOI: 10.1038/s41467-019-12515-9ISI: 000495858500001PubMedID: 31719529OAI: oai:DiVA.org:uu-398078DiVA, id: diva2:1374691
Available from: 2019-12-02 Created: 2019-12-02 Last updated: 2019-12-02Bibliographically approved

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