TY - JOUR
T1 - Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA
AU - Dahlqvist, Johanna
AU - Ekman, Diana
AU - Sennblad, Bengt
AU - Kozyrev, Sergey V
AU - Nordin, Jessika
AU - Karlsson, Åsa
AU - Meadows, Jennifer R S
AU - Hellbacher, Erik
AU - Rantapää-Dahlqvist, Solbritt
AU - Berglin, Ewa
AU - Stegmayr, Bernd
AU - Baslund, Bo
AU - Palm, Øyvind
AU - Haukeland, Hilde
AU - Gunnarsson, Iva
AU - Bruchfeld, Annette
AU - Segelmark, Mårten
AU - Ohlsson, Sophie
AU - Mohammad, Aladdin J
AU - Svärd, Anna
AU - Pullerits, Rille
AU - Herlitz, Hans
AU - Söderbergh, Annika
AU - Rosengren Pielberg, Gerli
AU - Hultin Rosenberg, Lina
AU - Bianchi, Matteo
AU - Murén, Eva
AU - Omdal, Roald
AU - Jonsson, Roland
AU - Eloranta, Maija-Leena
AU - Rönnblom, Lars
AU - Söderkvist, Peter
AU - Knight, Ann
AU - Eriksson, Per
AU - Lindblad-Toh, Kerstin
N1 - © The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.
PY - 2022/8/3
Y1 - 2022/8/3
N2 - 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.
AB - 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.
KW - Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/complications
KW - Antibodies, Antineutrophil Cytoplasmic
KW - Endothelial Cells
KW - Granulomatosis with Polyangiitis/complications
KW - Humans
KW - Microscopic Polyangiitis/complications
KW - Myeloblastin/genetics
KW - Peroxidase
UR - http://www.scopus.com/inward/record.url?scp=85138148342&partnerID=8YFLogxK
U2 - 10.1093/rheumatology/keab912
DO - 10.1093/rheumatology/keab912
M3 - Journal article
C2 - 34888651
SN - 1462-0324
VL - 61
SP - 3461
EP - 3470
JO - Rheumatology (Oxford, England)
JF - Rheumatology (Oxford, England)
IS - 8
ER -