Genetically Distinct Subsets within ANCA-Associated Vasculitis

Abstract

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.).

Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis

“…This association was limited to the GPA and PR3‐ANCA subsets (Table 2) and is consistent with prior GWAS data showing that a significant association with another SERPINA1 SNP, rs7151526, depended entirely on the concomitant presence of the Z allele 2.…”

“…A significant association of AAV with rs62132293, a SNP located 2.6 kb upstream of the PRTN3 transcription start site, was also observed ( P  = 8.60 × 10 −11 ); this finding is in keeping with previously observed associations at this locus (albeit with different SNPs) in AAV candidate gene and GWAS analyses (Table 1 and Supplementary Figures 3 and 4 [http://onlinelibrary.wiley.com/doi/10.1002/art.40034/abstract]) 2, 16. This association was limited to the GPA and PR3‐ANCA subsets (Table 2), consistent with the pathophysiologic relevance of the PRTN3 ‐encoded PR3 serine protease to these phenotypes 17.…”

“…Consistent with a prior study that demonstrated genetic distinctions between PR3‐ANCA–positive vasculitis and MPO‐ANCA–positive vasculitis 2, we detected peak associations of the HLA–DPB1 and HLA–DPA1 variants with positivity for PR3‐ANCAs, whereas in those with MPO‐ANCAs, the HLA–DQA2 and HLA–DQB1 variants showed the strongest associations. Differential effects of these variants also distinguished patients with GPA from those with MPA, suggesting that GPA and PR3‐ANCA–positive AAV share a composite set of MHC class II risk alleles that is largely distinct from those conferring risk of MPA and MPO‐ANCA–positive AAV.…”

Prevalence and Responsiveness to Treatment of Lung Abnormalities on Chest Computed Tomography in Patients With Microscopic Polyangiitis: A Multicenter, Longitudinal, Retrospective Study of One Hundred Fifty Consecutive Hospital‐Based Japanese Patients

“…This difference probably reflects the strong link between genetic background, AAV subtype, and ANCA subtype (15). Furthermore, the prevalence of pulmonary involvement in patients with MPA is higher in Japan than in European countries (5).…”

Vasculitis: do we know more to classify better?

“…These three AAV, especially GPA (WG) and MPA, are included in the same clinical studies. However, a recent genome-wide association study (GWAS) has provided evidence that GPA (WG) and MPA are indeed different diseases, while the strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome [27]. GPA (WG) is associated with different HLA genes compared with MPA, and singlenucleotide polymorphisms associated with the genes encoding α1-antitrypsin and proteinase 3 [27].…”