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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • European Vasculitis Genetics Consortium
Enheter & grupper
Externa organisationer
  • Health Data Research UK, Cambridge
  • University of Pisa
  • Jagellonian University
  • University of East Anglia
  • University of Cambridge
  • University of Milan
  • San Carlo Borromeo Hospital, Milan
  • NHSBT, Cambridge, United Kingdom
  • Parma University Hospital
  • University of Barcelona
  • Institutd' Investigacions Biomèdiques August Pi iSunyer (IDIBAPS)
  • Wellcome Trust Sanger Institute
  • University of Florence
  • Ruhr-University Bochum
  • Cochin Hospital
  • Karolinska University Hospital
  • Karolinska Institute
  • University of Lübeck
  • University of Melbourne
  • Murdoch Children's Research Institute
  • Tallaght University Hospital
  • Rheumazentrum Schleswig-Holstein Mitte
  • Kantonsspital St Gallen
  • Universitätsklinikum Jena
  • University Vita-Salute San Raffaele
  • San Raffaele Hospital
  • Friedrich-Alexander University Erlangen-Nürnberg
  • University Hospital Erlangen
  • University of Milano-Bicocca
  • Charles University in Prague
  • General University Hospital in Prague
  • Ipswich Hospital NHS Trust
  • Meyer Children's Hospital
  • Medical Research Council Biostatistics Unit
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Medicinsk genetik
Originalspråkengelska
Artikelnummer5120
TidskriftNature Communications
Volym10
StatusPublished - 2019 nov 12
PublikationskategoriForskning
Peer review utfördJa