Genetically Distinct Subsets within ANCA-Associated Vasculitis — NEJM.
Very interesting article on overlapping, uncommon, and enigmatic clinical syndromes that have an association with ANCA antibodies in common.
Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis is an uncommon condition encompassing two major well-characterized clinical syndromes: granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis) and microscopic polyangiitis. The pathogenesis is unknown and the exact role that ANCA plays in the pathogenesis of this disease in its various manifestations is unknown. It is even debatable whether this is even a single disease entity.
The authors performed a genomewide association study in a discovery cohort of 1233 patients in Britain with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls.
They found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and showed that granulomatosis with polyangiitis and microscopic polyangiitis are genetically distinct. Of most interest, the strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome.
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.