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

Paul Lyons ,William Astle,Mark A Little,Stephen Leslie,Richard M R Coulson,Giacomo Emmi,Kenneth G C Smith,Augusto Vaglio,Federico Alberici,Barbara Rewerska,Heather Elding,Loı̈c Guillevin ,Georg Schett,Peter Lamprecht,Damjan Vukcevic,James Liley,Thomas Neumann,Vladimı́r Tesař ,David Jayne ,Chiara Baldini,Benjamin Terrier ,Chris Wallace,Jörg T Epplen ,James E Peters ,Stefanie Quickert,María C Cid ,Tao Jiang,Wojciech Szczeklik,Sophie Ohlsson,Renato Alberto Sinico ,Francesco Bonatti,Frank Moosig,Iva Gunnarsson,Julia Holle ,Richard A Watts ,Giuseppe A Ramirez,Davide Martorana

doi: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.

Highlights

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)
Eosinophilic granulomatosis with polyangiitis (EGPA), once named Churg-Strauss syndrome, has a unique combination of clinical features that have some overlap with the other anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) syndromes, granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)[1,2]
We identified three genetic loci associated with EGPA at genome-wide significance (P < 5 × 10−8) (Fig. 1a, Supplementary Fig. 1, Table 2)

Summary

Introduction

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). We perform a genome-wide association study (GWAS) of EGPA It demonstrates that EGPA is polygenic with genetic distinctions between MPO ANCA positive (MPO+) and ANCAnegative disease, correlating with different clinical features. The genetic associations themselves point to dysregulation of pathways controlling eosinophil biology, severe asthma and vasculitis, beginning to explain the development and clinical features of disease. These results suggest that EGPA might be comprised of two distinct diseases defined by ANCA status, and provide a scientific rationale for targeted therapy

Methods

Results

Conclusion