1. Genetically Distinct Subsets within ANCA-Associated Vasculitis
- Author
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Bo Baslund, Paul A. Lyons, Mark A. Little, David Clayton, Andrew J. Rees, Iva Gunnarsson, Afzal N. Chaudhry, Augusto Vaglio, Mårten Segelmark, Loïc Guillevin, Zdenka Hruskova, Jochen Zwerina, Jan Willem Cohen Tervaert, Stefan Wieczorek, Kenneth G. C. Smith, Coen A. Stegeman, Paul Brenchley, Panos Deloukas, Vladimir Tesar, Tim F. Rayner, Caroline O. S. Savage, Wolfgang L. Gross, Lorraine Harper, Jan-Stephan F. Sanders, Benjamin Wilde, Julia U Holle, Alan D. Salama, David Jayne, Sapna Trivedi, Sandosh Padmanabhan, Sophie Ohlsson, Davide Martorana, Charles D. Pusey, Thomas Neumann, Annette Bruchfeld, Richard A. Watts, Conleth Feighery, Interne Geneeskunde, RS: CARIM School for Cardiovascular Diseases, RS: MHeNs School for Mental Health and Neuroscience, Groningen Kidney Center (GKC), Translational Immunology Groningen (TRIGR), and Groningen Institute for Organ Transplantation (GIOT)
- Subjects
Male ,HLA-DP Antigens ,Pathology ,Genotyping Techniques ,PATHOGENESIS ,Medizin ,Microscopic Polyangiitis ,Genome-wide association study ,DISEASE ,Major Histocompatibility Complex ,Pathogenesis ,0302 clinical medicine ,Risk Factors ,Proteinase 3 ,immune system diseases ,skin and connective tissue diseases ,PROTEINASE-3 ,ANTINEUTROPHIL CYTOPLASMIC AUTOANTIBODIES ,NEUTROPHILS ,0303 health sciences ,General Medicine ,3. Good health ,Female ,Granulomatosis with polyangiitis ,Vasculitis ,Microscopic polyangiitis ,ANTIBODY-ASSOCIATED VASCULITIS ,Systemic vasculitis ,medicine.medical_specialty ,Myeloblastin ,Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis ,SYSTEMIC VASCULITIS ,Polymorphism, Single Nucleotide ,SMALL-VESSEL VASCULITIS ,03 medical and health sciences ,WEGENERS-GRANULOMATOSIS ,medicine ,Humans ,Genetic Predisposition to Disease ,cardiovascular diseases ,GENOME-WIDE ASSOCIATION ,030304 developmental biology ,Anti-neutrophil cytoplasmic antibody ,030203 arthritis & rheumatology ,business.industry ,Granulomatosis with Polyangiitis ,medicine.disease ,respiratory tract diseases ,Case-Control Studies ,alpha 1-Antitrypsin ,Immunology ,business ,Genome-Wide Association Study - Abstract
BACKGROUNDAntineutrophil 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.METHODSA 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.RESULTSWe 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)).CONCLUSIONSThis 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.)
- Published
- 2012