Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status
Articolo
Data di Pubblicazione:
2019
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.
Tipologia CRIS:
03A-Articolo su Rivista
Keywords:
Antibodies, Antineutrophil Cytoplasmic; Eosinophils; Genetic Association Studies; Granulomatosis with Polyangiitis; Humans; Mendelian Randomization Analysis; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study
Elenco autori:
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.; Akil M.; Barratt J.; Basu N.; Butterworth A.S.; Bruce I.; Clarkson M.; Conlon N.; DasGupta B.; Doulton T.W.R.; Espigol-Frigole G.; Flossmann O.; Gabrielli A.; Gasior J.; Gregorini G.; Guida G.; Hernandez-Rodriguez J.; Hruskova Z.; Hudson A.; Knight A.; Lanyon P.; Luqmani R.; Magliano M.; Manfredi A.A.; Marguerie C.; Maritati F.; Marvisi C.; McHugh N.J.; Molloy E.; Motyer A.; Mukhtyar C.; Padyukov L.; Pesci A.; Prieto-Gonzalez S.; Ramentol-Sintas M.; Reis P.; Roccatello D.; Rovere-Querini P.; Salvarani C.; Santarsia F.; Solans-Laque R.; Soranzo N.; Taylor J.; Wessels J.; Zwerina J.; Terrier B.; Watts R.A.; Vaglio A.; Holle J.U.; Wallace C.; Smith K.G.C.
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