Identification of a Novel Susceptibility Locus for Small Vessel Vasculitis with Autoantibodies Against Myeloperoxidase

Johanna Dahlqvist¹, Diana Ekman², Bengt Sennblad², Sergey Kozyrev³, Jessika Nordin², Åsa Karlsson³, Jennifer Meadows³, Erik Hellbacher¹, Solbritt Rantapaa-Dahlqvist⁴, Ewa Berglin⁵, Bernd Stegmayr⁵, Bo Baslund⁶, Øyvind Palm⁷, Hilde Haukeland⁷, Iva Gunnarsson⁸, Annette Bruchfeld⁸, Mårten Segelmark⁹, Sophie Ohlsson⁹, Aladdin Mohammad⁹, Anna Svärd¹⁰, Rille Pullerits¹¹, Hans Herlitz¹¹, Annika Söderbergh¹², Gerli Rosengren Pielberg³, Fabiana Farias³, Lina Hultin Rosenberg³, Matteo Bianchi³, Eva Muren³, Roald Omdal¹³, Roland Jonsson¹⁴, Maija-Leena Eloranta³, Lars Ronnblom³, Peter Söderkvist¹⁵, Ann Knight¹⁶, Per Eriksson¹⁵ and Kerstin Lindblad-Toh¹⁷, ¹Uppsala University and University Hospital, Uppsala, Sweden, ²Science for Life Laboratory, Uppsala University, Uppsala, Sweden, ³Uppsala University, Uppsala, Sweden, ⁴Ume University, Umea, Sweden, ⁵Umeå University and University Hospital, Umeå, Sweden, ⁶University of Copenhagen, Copenhagen, Denmark, ⁷Oslo University, Oslo, Norway, ⁸Karolinska Institute, Stockholm, Sweden, ⁹Lund University, Lund, Sweden, ¹⁰Uppsala University, Falun, Sweden, ¹¹Gothenburg University and Sahlgrenska Hospital, Gothenburg, Sweden, ¹²Dept. of Rheumatology, Örebro University Hospital, Örebro, Sweden, ¹³Stavanger University Hospital and University of Bergen, Stavanger, Norway, ¹⁴University of Bergen, Bergen, Norway, ¹⁵Linköping University, Linköping, Sweden, ¹⁶Rheumatology, Institute of Medical Sciences, Uppsala University, Uppsala, Sweden, ¹⁷Broad Institute of MIT and Harvard; and Uppsala University, Boston, MA

Meeting: ACR Convergence 2021

Keywords: ANCA associated vasculitis, genetics

Session Information

Date: Sunday, November 7, 2021

Title: Genetics, Genomics & Proteomics Poster (0517–0533)

Session Type: Poster Session B

Session Time: 8:30AM-10:30AM

Background/Purpose: ANCA-associated vasculitides (AAV) are rare but aggressive autoimmune disorders. The pathogenesis of the disorders is complex and still poorly understood; only a few genetic loci have been associated with AAV. The aim of this project was to identify and characterize novel susceptibility loci for AAV positive for myeloperoxidase (MPO) or proteinase 3 (PR3) ANCA.

Methods: Genetic association analyses were performed after Illumina sequencing of 1853 genes and subsequent replication with genotyping of candidate single-nucleotide polymorphisms (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 analyzed for allele-specific effects on gene expression using luciferase reporter assay.

Results: Associations between PR3-ANCA positive AAV and the HLA-DPB1, HLA-DPA1 and SERPINA1 genes and between MPO-ANCA positive AAV and the HLA–DQB1 locus identified in previous genome-wide studies were confirmed in the present study. In addition, a novel locus on chromosome 6 was identified as associated with MPO-ANCA positive AAV. The rare allele of the novel disease-associated SNP affected downstream gene expression in a cell type specific manner.

Conclusion: This study confirms previous findings of genetic associations specific for PR3-ANCA positive and MPO-ANCA positive AAV, respectively. A novel susceptibility locus for MPO-ANCA positive AAV was identified, where the disease-associated SNP may facilitate the development of autoimmunity through a negative effect on the expression of the closest gene in specific cell types.

Disclosures: J. Dahlqvist, None; D. Ekman, None; B. Sennblad, None; S. Kozyrev, None; J. Nordin, None; . Karlsson, None; J. Meadows, None; E. Hellbacher, None; S. Rantapaa-Dahlqvist, None; E. Berglin, None; B. Stegmayr, None; B. Baslund, None; . Palm, None; H. Haukeland, None; I. Gunnarsson, None; A. Bruchfeld, None; M. Segelmark, None; S. Ohlsson, None; A. Mohammad, Roche, 6, Amgen, 1, Vifor, 6, Lilly, 6; A. Svärd, None; R. Pullerits, None; H. Herlitz, None; A. Söderbergh, Roche, 6; G. Rosengren Pielberg, None; F. Farias, None; L. Hultin Rosenberg, None; M. Bianchi, None; E. Muren, None; R. Omdal, None; R. Jonsson, None; M. Eloranta, None; L. Ronnblom, None; P. Söderkvist, None; A. Knight, None; P. Eriksson, None; K. Lindblad-Toh, None.

To cite this abstract in AMA style:

Dahlqvist J, Ekman D, Sennblad B, Kozyrev S, Nordin J, Karlsson , Meadows J, Hellbacher E, Rantapaa-Dahlqvist S, Berglin E, Stegmayr B, Baslund B, Palm , Haukeland H, Gunnarsson I, Bruchfeld A, Segelmark M, Ohlsson S, Mohammad A, Svärd A, Pullerits R, Herlitz H, Söderbergh A, Rosengren Pielberg G, Farias F, Hultin Rosenberg L, Bianchi M, Muren E, Omdal R, Jonsson R, Eloranta M, Ronnblom L, Söderkvist P, Knight A, Eriksson P, Lindblad-Toh K. Identification of a Novel Susceptibility Locus for Small Vessel Vasculitis with Autoantibodies Against Myeloperoxidase [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 9). https://acrabstracts.org/abstract/identification-of-a-novel-susceptibility-locus-for-small-vessel-vasculitis-with-autoantibodies-against-myeloperoxidase/. Accessed .

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