Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA
| Autor: | Johanna Dahlqvist, Diana Ekman, Bengt Sennblad, Sergey V Kozyrev, Jessika Nordin, Åsa Karlsson, Jennifer R S Meadows, Erik Hellbacher, Solbritt Rantapää-Dahlqvist, Ewa Berglin, Bernd Stegmayr, Bo Baslund, Øyvind Palm, Hilde Haukeland, Iva Gunnarsson, Annette Bruchfeld, Mårten Segelmark, Sophie Ohlsson, Aladdin J Mohammad, Anna Svärd, Rille Pullerits, Hans Herlitz, Annika Söderbergh, Gerli Rosengren Pielberg, Lina Hultin Rosenberg, Matteo Bianchi, Eva Murén, Roald Omdal, Roland Jonsson, Maija-Leena Eloranta, Lars Rönnblom, Peter Söderkvist, Ann Knight, Per Eriksson, Kerstin Lindblad-Toh |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Reumatologi och inflammation
ANCA-associated vasculitis PR3-ANCA MPO-ANCA genetic analysis BACH2 regulatory variant Myeloblastin Granulomatosis with Polyangiitis Endothelial Cells Microscopic Polyangiitis Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/complications Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis Myeloblastin/genetics Antibodies Antineutrophil Cytoplasmic Granulomatosis with Polyangiitis/complications Rheumatology Microscopic Polyangiitis/complications Humans Pharmacology (medical) Medical Genetics ANCA-Associated vasculitis Medicinsk genetik Rheumatology and Autoimmunity Peroxidase |
| Zdroj: | Rheumatology Dahlqvist, J, Ekman, D, Sennblad, B, Kozyrev, S V, Nordin, J, Karlsson, Å, Meadows, J R S, Hellbacher, E, Rantapää-Dahlqvist, S, Berglin, E, Stegmayr, B, Baslund, B, Palm, Ø, Haukeland, H, Gunnarsson, I, Bruchfeld, A, Segelmark, M, Ohlsson, S, Mohammad, A J, Svärd, A, Pullerits, R, Herlitz, H, Söderbergh, A, Rosengren Pielberg, G, Hultin Rosenberg, L, Bianchi, M, Murén, E, Omdal, R, Jonsson, R, Eloranta, M-L, Rönnblom, L, Söderkvist, P, Knight, A, Eriksson, P & Lindblad-Toh, K 2022, ' Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA ', Rheumatology, vol. 61, no. 8, pp. 3461-3470 . https://doi.org/10.1093/rheumatology/keab912 |
| DOI: | 10.1093/rheumatology/keab912 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|