Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA
Dahlqvist, Johanna; Ekman, Diana; Sennblad, Bengt; Kozyrev, Sergey V.; Nordin, Jessika; Karlsson, Åsa; Meadows, Jennifer R. S.; Hellbacher, Erik; Rantapää-Dahlqvist, Solbritt; Berglin, Ewa; Stegmayr, Bernd; Haslund, Bo; Palm, Øyvind; Haukeland, Hilde; Gunnarsson, Iva; Bruchfeld, Annette; Segelmark, Mårten; Ohlsson, Sophie; Mohammad, Aladdin J.; Svärd, Anna Jessica; Pullerits, Rille; Herlitz, Hans; Söderbergh, Annika; Pielberg, Gerli Rosengren; Rosenberg, Lina Hultin; Bianchi, Matteo; Muren, Eva; Omdal, Roald; Jonsson, Roland; Eloranta, Maija-Leena; Rönnblom, Lars; Söderkvist, Peter; Knight, Ann; Eriksson, Per; Lindblad-Toh, Kerstin
Journal article, Peer reviewed
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OriginalversjonRheumatology. 2021 10.1093/rheumatology/keab912
Objective To identify and characterize genetic loci associated with the risk of developing ANCA-associated vasculitides (AAV). Methods Genetic association analyses were performed after Illumina sequencing of 1853 genes and subsequent replication with genotyping of selected single nucleotide polymorphisms in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis or microscopic polyangiitis, and 1589 controls. A novel AAV-associated single nucleotide polymorphism was analysed for allele-specific effects on gene expression using luciferase reporter assay. Results PR3-ANCA+ AAV was significantly associated with two independent loci in the HLA-DPB1/HLA-DPA1 region [rs1042335, P = 6.3 × 10−61, odds ratio (OR) 0.10; rs9277341, P = 1.5 × 10−44, OR 0.22] and with rs28929474 in the SERPINA1 gene (P = 2.7 × 10−10, OR 2.9). MPO-ANCA+ AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, P = 5.4 × 10−25, OR 3.7) and with a rare variant in the BACH2 gene (rs78275221, P = 7.9 × 10−7, OR 3.0), the latter a novel susceptibility locus for MPO-ANCA+ granulomatosis with polyangiitis/microscopic polyangiitis. 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.