Identification and Functional Characterization of a Novel Susceptibility Locus for Small Vessel Vasculitis with MPO-ANCA.

Dahlqvist J, Ekman D, Sennblad B, Kozyrev SV, Nordin J, Karlsson Å, Meadows JRS, Hellbacher E, Rantapää-Dahlqvist S, Berglin E, Stegmayr B, Baslund B, Palm Ø, Haukeland H, Gunnarsson I, Bruchfeld A, Segelmark M, Ohlsson S, Mohammad AJ, Svärd A, Pullerits R, Herlitz H, Söderbergh A, Rosengren Pielberg G, Hultin Rosenberg L, Bianchi M, Murén E, Omdal R, Jonsson R, Eloranta ML, Rönnblom L, Söderkvist P, Knight A, Eriksson P, Lindblad-Toh K

Rheumatology (Oxford) - (-) - [2021-12-09; online 2021-12-09]

To identify and characterize genetic loci associated with the risk of developing anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). Genetic association analyses were performed after Illumina sequencing of 1,853 genes and subsequent replication with genotyping of selected SNPs in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) and 1589 controls. A novel AAV-associated SNP was analysed for allele-specific effects on gene expression using luciferase reporter assay. Proteinase 3 ANCA positive (PR3-ANCA+) AAV was significantly associated with two independent loci in the HLA-DPB1/A1 region (rs1042335, p= 6.3 x 1 0 -61, Odds ratio (OR)= 0.10; rs9277341, p= 1.5 x 1 0 -44, OR = 0.22) and with rs28929474 in the SERPINA1 gene (p= 2.7 x 1 0 -10, OR = 2.9). Myeloperoxidase (MPO)-ANCA+ AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, p= 5.4 x 1 0 -25, OR = 3.7) and with a rare variant in the BACH2 gene (rs78275221, p= 7.9 x 1 0 -7, OR = 3.0), the latter a novel susceptibility locus for MPO-ANCA+ GPA/MPA. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele. 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.

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PubMed 34888651

DOI 10.1093/rheumatology/keab912

Crossref 10.1093/rheumatology/keab912

pii: 6458341

Publications 7.1.2