Genetically distinct subsets within ANCA-associated vasculitis

Lyons, Paul A., Rayner, Tim F., Trivedi, Sapna, Holle, Julia U., Watts, Richard A., Jayne, David R. W., Baslund, Bo, Brenchley, Paul, Bruchfeld, Annette, Chaudhry, Afzal N., Cohen Tervaert, Jan Willem and Deloukas, Panos (2012) Genetically distinct subsets within ANCA-associated vasculitis. New England Journal of Medicine, 367. pp. 214-223. ISSN 1533-4406

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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.

Item Type: Article
Additional Information: Funding information: Supported by grants from the British Heart Foundation (SP/09/001/27117, to Dr. Smith); the Wellcome Trust (083650/Z/07/Z, to Dr. Smith); the National Institute of Health Research Biomedical Research Centres of Cambridge, Imperial College, and Manchester; the Medical Research Council and Kidney Research UK (to Drs. Rees and Pusey); the West Anglia Comprehensive Local Research Network (to Drs. Smith and Jayne); the Norfolk and Suffolk Comprehensive Local Research Network (to Dr. Watts); and the German Research Foundation (KFO170, to Drs. Holle and Wieczorek); and by a contract from the European Union FP7 Infectious Triggers of Chronic Autoimmunity Consortium (CP-FP 261382, to Drs. Smith, Lyons, and Rees).
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Musculoskeletal Medicine
Faculty of Medicine and Health Sciences > Research Groups > Epidemiology and Public Health
Faculty of Medicine and Health Sciences > Research Groups > Public Health and Health Services Research (former - to 2023)
Depositing User: Pure Connector
Date Deposited: 05 Sep 2013 05:25
Last Modified: 04 Jan 2024 02:49
DOI: 10.1056/NEJMoa1108735

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