The HLA-DPB1*0401 allele, the PI*Z allele of the gene encoding α1-antitrypsin (SERPINA1) and the proteinase 3 (PRTN3) gene have been associated with GPA.
Among six patients without granuloma on nasal biopsy, three patients with only antineutrophil cytoplasmic antibody (ANCA) and chronic rhinosinusitis could be classified as GPA due to proteinase 3 (PR3)-ANCA (or cytoplasmic (C)-ANCA) positivity.
Proteinase 3 (PR3), the target antigen of antineutrophil cytoplasm autoantibodies, which are found in patients with Wegener granulomatosis, is a neutrophil serine protease localized within cytoplasmic granules.
Granuloma formation, as seen in PR3-ANCA-associated GPA, is not well explained by the presence of autoantibodies in experimental models.Here, T cells seem crucial.
Among antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), granulomatosis with polyangiitis (GPA) and proteinase 3-ANCA-positive AAV (PR3-AAV) are prevalent in European populations, while microscopic polyangiitis (MPA) and myeloperoxidase-ANCA-positive AAV (MPO-AAV) are predominant in the Japanese.
All but one patient, who had concomitant C-ANCA seropositivity and granulomatosis with polyangiitis, had a favorable disease course with controlled inflammation using topical and/or systemic immunomodulatory therapy.
This study excludes certain PR3 epitope variants as autoantigenic stimuli in WG, since the Val119Ile polymorphism showed no differences between patients and controls.
Association of ETS1 polymorphism with granulomatosis with polyangiitis and proteinase 3-anti-neutrophil cytoplasmic antibody positive vasculitis in a Japanese population.
We examined five additional SNPs and a sixth SNP haplotype within the PRTN3 promoter region in a family-based association analysis and found no evidence that mutations within PRTN3 are associated with WG diagnosis.
Moreover, we identified genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis and between proteinase 3 ANCA vasculitis and myeloperoxidase ANCA vasculitis.
The previously reported strong association of WG with the HLA-DPB1*0401 allele was confirmed in an independent WG sample (n = 108, p(c) = 6.4 x 10(-8)).
A trend toward increased frequency of DPB1*04:01, the risk allele for GPA in European populations, was observed among Japanese patients with PR3-AAV when conditioned on DRB1*13:02 (Padjusted = 0.0021, ORadjusted = 3.48).
In addition, these studies have also shown that different AAV subtypes such as granulomatosis with polyangiitis (Wegener's, GPA) and microscopic polyangiitis (MPA) are underpinned by distinct genetic risk factors, with GPA being associated with HLA-DP, SERPINA1 (encoding α1-antitrypsin), PRTN3 (encoding proteinase-3, PR3, the main GPA-related autoantigen) and SEMA6A (semaphorin 6A), whereas MPA has been mainly associated with HLA-DQ.
Our results in American patients confirm findings from a Scandinavian cohort in which a positive association between WG and longer alleles of (AT)n in the Ctla4 3'-UTR was demonstrated.
Furthermore, the non-carriage of CTLA-4 allele 86 was associated with WG formation, while homocygotic carriage of the CCR5 allele delta 32 seemed to prevent ANCA-negative WG.
The distribution of cytokine and cytotoxic T cell antigen 4 (CTLA4) gene polymorphisms and HLA class II alleles was analysed in 32 patients with generalised WG and 91 healthy controls.
The disease is associated with expanded dinucleotide repeats in the cytotoxic T lymphocyte antigen 4 (CTLA-4) gene, suggesting that genetic variation(s) in T cell related gene(s) could contribute to the T cell hyperactivity in WG.