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Genetically Distinct Subsets within ANCA-Associated Vasculitis
Addenbrookes Hospital, England.
Addenbrookes Hospital, England.
Addenbrookes Hospital, England.
University Hospital Schleswig Holstein, Germany.
Show others and affiliations
2012 (English)In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 367, no 3, 214-223 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND less thanbrgreater than less thanbrgreater thanAntineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegeners 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. less thanbrgreater than less thanbrgreater thanMETHODS less thanbrgreater than less thanbrgreater thanA 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. less thanbrgreater than less thanbrgreater thanRESULTS less thanbrgreater than less thanbrgreater thanWe 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 alpha(1)-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P = 6.2x10(-89), P = 5.6x10(-12), and P = 2.6x10(-7), respectively). Anti-myeloperoxidase ANCA was associated with HLA-DQ (P = 2.1x10(-8)). less thanbrgreater than less thanbrgreater thanCONCLUSIONS less thanbrgreater than less thanbrgreater thanThis 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.)

Place, publisher, year, edition, pages
Massachusetts Medical Society , 2012. Vol. 367, no 3, 214-223 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-79637DOI: 10.1056/NEJMoa1108735ISI: 000306522900005OAI: oai:DiVA.org:liu-79637DiVA: diva2:543973
Note
Funding Agencies|British Heart Foundation|SP/09/001/27117|Wellcome Trust|083650/Z/07/Z|National Institute of Health Research Biomedical Research Centres of Cambridge, Imperial College, and Manchester||Medical Research Council||Kidney Research UK||West Anglia Comprehensive Local Research Network||Norfolk and Suffolk Comprehensive Local Research Network||German Research Foundation|KFO170|European Union|CP-FP 261382|Available from: 2012-08-13 Created: 2012-08-13 Last updated: 2017-12-07

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Segelmark, Mårten

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CiteExportLink to record
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