Genetically distinct subsets within ANCA-associated vasculitis

Paul A. Lyons, Tim F. Rayner, Sapna Trivedi, Julia U. Holle, Richard A. Watts, David R.W. Jayne, Bo Baslund, Paul Brenchley, Annette Bruchfeld, Afzal N. Chaudhry, Jan Willem Cohen Tervaert, Panos Deloukas, Conleth Feighery, Wolfgang L. Gross, Loic Guillevin, Iva Gunnarsson, Lorraine Harper, Zdenka Hrušková, Mark A. Little, Davide MartoranaThomas Neumann, Sophie Ohlsson, Sandosh Padmanabhan, Charles D. Pusey, Alan D. Salama, Jan Stephan F. Sanders, Caroline O. Savage, Mårten Segelmark, Coen A. Stegeman, Vladimir Tesař, Augusto Vaglio, Stefan Wieczorek, Benjamin Wilde, Jochen Zwerina, Andrew J. Rees, David G. Clayton, Kenneth G.C. Smith*

*Corresponding author for this work
380 Citations (Scopus)

Abstract

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis. Methods: A genomewide association study was performed in a discovery cohort of 1233 U.K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria. Results: We found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti-proteinase 3 ANCA was associated with HLA-DP and the genes encoding α1- antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P = 6.2×10-89, P = 5.6×10 -12, and P = 2.6×10-7, respectively). Anti-myeloperoxidase ANCA was associated with HLA-DQ (P = 2.1×10 -8). Conclusions: This study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA-associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.)

Original languageEnglish
JournalNew England Journal of Medicine
Volume367
Issue number3
Pages (from-to)214-223
Number of pages10
ISSN0028-4793
DOIs
Publication statusPublished - 19.07.2012

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