Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA.
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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
Аннотация
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.