Genetically Distinct Subsets Within ANCA-Associated Vasculitis

Study Questions:

What are the genetic risk factors and background for granulomatosis with polyangiitis and microscopic polyangiitis?


A genomewide association study was performed in a discovery cohort of 1,233 UK patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and 5,884 controls, and was replicated in 1,454 Northern European case patients and 1,666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria. Single-nucleotide polymorphism (SNP) association was determined by applying a standard 1-degree-of-freedom Cochran–Armitage test for additive association.


The investigators 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).


The authors concluded that the pathogenesis of ANCA-associated vasculitis has a genetic component and shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis.


This genomewide association study of patients with ANCA-associated vasculitis shows that there is a significant genetic contribution to pathogenesis of the disease, which differs between granulomatosis with polyangiitis and microscopic polyangiitis. These data further suggest that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA–associated vasculitis, and provide support for the concept that proteinase 3 ANCA–associated vasculitis and myeloperoxidase ANCA–associated vasculitis are distinct autoimmune syndromes. Future genetic and clinical studies of ANCA-associated vasculitis should be sufficiently powered to allow for independent analysis of proteinase 3–ANCA and myeloperoxidase-ANCA polyangiitis since subsets defined by ANCA specificity may respond differently to therapeutic interventions.

Clinical Topics: Anticoagulation Management, Dyslipidemia, Heart Failure and Cardiomyopathies, Vascular Medicine, Lipid Metabolism, Novel Agents, Heart Failure and Cardiac Biomarkers

Keywords: Myeloblastin, Vasculitis, Genome-Wide Association Study, Antibodies, Antineutrophil Cytoplasmic, Benzoxazoles, Autoantigens, HLA-DQ Antigens, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Polymorphism, Single Nucleotide, Thromboplastin, Cardiology, Peroxidase, HLA-DP Antigens, HLA Antigens, Systemic Vasculitis, Wegener Granulomatosis, Microscopic Polyangiitis

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