학술논문
Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA
Document Type
Author
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
Source
Rheumatology. 61(8):3461-3470
Subject
Language
English
ISSN
1462-0324
Abstract
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.