Genetically Distinct Subsets within ANCA-Associated Vasculitis
(2012) In New England Journal of Medicine 367(3). p.214-223- 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.... (More)
- 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 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)). 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.) (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/2991588
- author
- 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.
; Tervaert, Jan Willem Cohen
; Deloukas, Panos
; Feighery, Conleth
; Gross, Wolfgang L.
; Guillevin, Loic
; Gunnarsson, Iva
; Harper, Lorraine
; Hruskova, Zdenka
; Little, Mark A.
; Martorana, Davide
; Neumann, Thomas
; Ohlsson, Sophie
LU
; Padmanabhan, Sandosh
; Pusey, Charles D.
; Salama, Alan D.
; Sanders, Jan-Stephan F.
; Savage, Caroline O.
; Segelmark, Mårten
LU
; Stegeman, Coen A.
; Tesar, Vladimir
; Vaglio, Augusto
; Wieczorek, Stefan
; Wilde, Benjamin
; Zwerina, Jochen
; Rees, Andrew J.
; Clayton, David G.
and Smith, Kenneth G. C.
(Less) - organization
- publishing date
- 2012
- type
- Contribution to journal
- publication status
- published
- subject
- in
- New England Journal of Medicine
- volume
- 367
- issue
- 3
- pages
- 214 - 223
- publisher
- Massachusetts Medical Society
- external identifiers
-
- wos:000306522900005
- scopus:84864014453
- pmid:22808956
- ISSN
- 0028-4793
- DOI
- 10.1056/NEJMoa1108735
- language
- English
- LU publication?
- yes
- id
- e4eae75c-3198-4a4a-b27d-d3cd2c82f3d6 (old id 2991588)
- date added to LUP
- 2016-04-01 10:40:54
- date last changed
- 2022-04-28 00:00:03
@article{e4eae75c-3198-4a4a-b27d-d3cd2c82f3d6,
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 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)). 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.)}},
author = {{Lyons, Paul A. and Rayner, Tim F. and Trivedi, Sapna and Holle, Julia U. and Watts, Richard A. and Jayne, David R. W. and Baslund, Bo and Brenchley, Paul and Bruchfeld, Annette and Chaudhry, Afzal N. and Tervaert, Jan Willem Cohen and Deloukas, Panos and Feighery, Conleth and Gross, Wolfgang L. and Guillevin, Loic and Gunnarsson, Iva and Harper, Lorraine and Hruskova, Zdenka and Little, Mark A. and Martorana, Davide and Neumann, Thomas and Ohlsson, Sophie and Padmanabhan, Sandosh and Pusey, Charles D. and Salama, Alan D. and Sanders, Jan-Stephan F. and Savage, Caroline O. and Segelmark, Mårten and Stegeman, Coen A. and Tesar, Vladimir and Vaglio, Augusto and Wieczorek, Stefan and Wilde, Benjamin and Zwerina, Jochen and Rees, Andrew J. and Clayton, David G. and Smith, Kenneth G. C.}},
issn = {{0028-4793}},
language = {{eng}},
number = {{3}},
pages = {{214--223}},
publisher = {{Massachusetts Medical Society}},
series = {{New England Journal of Medicine}},
title = {{Genetically Distinct Subsets within ANCA-Associated Vasculitis}},
url = {{https://lup.lub.lu.se/search/files/2047981/3127188.pdf}},
doi = {{10.1056/NEJMoa1108735}},
volume = {{367}},
year = {{2012}},
}