Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA
| العنوان: | Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA |
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| المؤلفون: | Dahlqvist, Johanna, Ekman, Diana, Sennblad, Bengt, Kozyrev, Sergey V, Nordin, Jessika, Karlsson, Åsa, Meadows, Jennifer R. S, Hellbacher, Erik, Rantapää-Dahlqvist, Solbritt, Berglin, Ewa, MD, PhD, 1955, Stegmayr, Bernd, 1949, Baslund, Bo, Palm, Øyvind, Haukeland, Hilde, Gunnarsson, Iva, Bruchfeld, Annette, Segelmark, Mårten, Ohlsson, Sophie, Mohammad, Aladdin J, Svärd, Anna, Pullerits, Rille, Herlitz, Hans, Söderbergh, Annika, Rosengren Pielberg, Gerli, Hultin Rosenberg, Lina, Bianchi, Matteo, Muren, Eva, Omdal, Roald, Jonsson, Roland, Eloranta, Maija-Leena, Rönnblom, Lars, Söderkvist, Peter, Knight, Ann, Eriksson, Per, Lindblad-Toh, Kerstin |
| المصدر: | Rheumatology. 61(8):3461-3470 |
| مصطلحات موضوعية: | ANCA-Associated vasculitis, BACH2, genetic analysis, MPO-ANCA, PR3-ANCA, regulatory variant |
| الوصف: | 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. |
| وصف الملف: | electronic |
| URL الوصول: | https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-211837 https://doi.org/10.1093/rheumatology/keab912 https://umu.diva-portal.org/smash/get/diva2:1781802/FULLTEXT01.pdf |
| قاعدة البيانات: | SwePub |
| تدمد: | 14620324 |
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| DOI: | 10.1093/rheumatology/keab912 |