Genetically distinct subsets within ANCA-associated vasculitis
Paul A Lyons1, Tim F Rayner, Sapna Trivedi
1Cambridge Institute for Medical Research, and Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom. kgcs2@cam.ac.uk
The New England Journal of Medicine
|July 20, 2012
Summary
Genetic factors influence ANCA-associated vasculitis, with distinct genetic profiles for granulomatosis with polyangiitis and microscopic polyangiitis linked to ANCA specificity. This suggests separate autoimmune syndromes based on autoantigen targets like proteinase 3.
Area of Science:
- Genetics
- Immunology
- Rheumatology
Background:
- Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis encompasses granulomatosis with polyangiitis and microscopic polyangiitis, with unknown etiology and debated disease classification.
- The role of ANCA in pathogenesis and the potential for a single disease entity remain subjects of investigation.
Purpose of the Study:
- To investigate the genetic basis of ANCA-associated vasculitis.
- To determine if granulomatosis with polyangiitis and microscopic polyangiitis are genetically distinct.
- To identify genetic associations with ANCA specificity.
Main Methods:
- A genomewide association study was conducted in a discovery cohort of 1233 U.K. patients and 5884 controls.
- Replication analysis involved 1454 Northern European case patients and 1666 controls.
- Standard quality control, population stratification, and statistical analyses were applied.
Main Results:
- Significant major-histocompatibility-complex (MHC) and non-MHC genetic associations with ANCA-associated vasculitis were identified.
- Granulomatosis with polyangiitis and microscopic polyangiitis demonstrated distinct genetic profiles.
- Strongest associations were with ANCA antigenic specificity: anti-proteinase 3 ANCA linked to HLA-DP, SERPINA1, and PRTN3; anti-myeloperoxidase ANCA linked to HLA-DQ.
Conclusions:
- The pathogenesis of ANCA-associated vasculitis has a significant genetic component.
- Genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis correlate with ANCA specificity.
- The findings support proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis as distinct autoimmune syndromes.
