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

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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.

authors

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

publication date

  • December 2019