Identification and Functional Characterization of a Novel Susceptibility Locus for Small Vessel Vasculitis with MPO-ANCA

OBJECTIVE: To identify and characterize genetic loci associated with the risk of developing anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV).METHODS: Genetic association analyses were performed after Illumina sequencing of 1,853 genes and subsequent replication with genotyping of selected SNPs in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) and 1589 controls. A novel AAV-associated SNP was analysed for allele-specific effects on gene expression using luciferase reporter assay.RESULTS: Proteinase 3 ANCA positive (PR3-ANCA+) AAV was significantly associated with two independent loci in the HLA-DPB1/A1 region (rs1042335, p= 6.3 x 1 0 -61, Odds ratio (OR)= 0.10; rs9277341, p= 1.5 x 1 0 -44, OR = 0.22) and with rs28929474 in the SERPINA1 gene (p= 2.7 x 1 0 -10, OR = 2.9). Myeloperoxidase (MPO)-ANCA+ AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, p= 5.4 x 1 0 -25, OR = 3.7) and with a rare variant in the BACH2 gene (rs78275221, p= 7.9 x 1 0 -7, OR = 3.0), the latter a novel susceptibility locus for MPO-ANCA+ GPA/MPA. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele.CONCLUSION: We identified a novel susceptibility locus for MPO-ANCA+ AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types