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

Little, Mark; Conlon, Niall

doi:http://dx.doi.org/10.1038/s41467-019-12515-9

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

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Lyons_et_al-2019-Nature_Communications.pdf (1.48 MB)

Date

2019

Authors

Little, Mark

Conlon, Niall

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openAccess

Citation

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.A., Rewerska B., Schett G., Sinico R.A., Szczeklik W., Tesar V., Vukcevic D., Terrier B., Watts R.A., Vaglio A., Holle J.U., Wallace C., Smith K.G.C., Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status, Nature communications, 10, 1, 2019, 5120-

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.