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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 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 polymo...

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Detalles Bibliográficos
Autores principales: 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, 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, Murén, Eva, Omdal, Roald, Jonsson, Roland, Eloranta, Maija-Leena, Rönnblom, Lars, Söderkvist, Peter, Knight, Ann, Eriksson, Per, Lindblad-Toh, Kerstin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9348767/
https://www.ncbi.nlm.nih.gov/pubmed/34888651
http://dx.doi.org/10.1093/rheumatology/keab912
Descripción
Sumario: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.