Proceedings of the 20th International Vasculitis and ANCA conference - Dublin
Published March 31, 2022 | Version v1
Other Open

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

Authors/Creators

  • 1. Peter Söderkvist18, Ann Knight1, Per Eriksson18, Kerstin Lindblad-Toh2,19 1Dep. of Medical Sciences, Uppsala University, Uppsala, Sweden, 2Dep. of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
  • 2. 3Dep. of Biochemistry and Biophysics, National Bioinformatics Infrastructure Sweden, Stockholm University, Stockholm, Sweden
  • 3. 4Dep. of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Uppsala University, Uppsala, Sweden
  • 4. 2Dep. of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
  • 5. 1Dep. of Medical Sciences, Uppsala University, Uppsala,
  • 6. 5Dep. of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
  • 7. 6Copenhagen Lupus and Vasculitis Clinic, Copenhagen University Hospital, Copenhagen, Denmark
  • 8. 7Dep. of Rheumatology, Oslo University Hospital, Oslo, Norway
  • 9. 8Dep. of Rheumatology, Martina Hansens Hospital, Oslo, Norway
  • 10. 9Dep. of Medicine, Karolinska Institutet, Stockholm, Sweden
  • 11. 10Dep. of Health, Linköping University, Linköping, Sweden
  • 12. 11Dep. of Clinical Sciences, Lund University, Lund, Sweden
  • 13. 12Center for Clinical Research Dalarna, Uppsala University, Uppsala, Sweden
  • 14. 13Dep. of Rheumatology and Inflammation Research, University of Gothenburg, Gothenburg, Sweden
  • 15. 14Dep. of Molecular and Clinical Medicine/Nephrology, University of Gothenburg, Gothenburg, Sweden
  • 16. 15Dep. of Rheumatology, Örebro University Hospital, Örebro, Sweden
  • 17. 16Dep. of Internal Medicine, Stavanger University Hospital, Stavanger, Norway, 17Dep. of Clinical Science, University of Bergen, Bergen, Norway
  • 18. 17Dep. of Clinical Science, University of Bergen, Bergen, Norway
  • 19. 18Dep. of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
  • 20. 2Dep. of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden; 19Broad Institute of MIT and Harvard University, Cambridge, USA

Description

Background: 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. Data were analysed using logistic regression with a P value threshold for significance of < 9.1 x 10-7. A novel AAV-associated SNP was analysed 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+ AAV and the HLA–DQB1 locus identified in previous genome-wide studies were confirmed in the present study. In addition, a rare SNP located in the BACH2 gene (rs78275221) was identified as significantly associated with MPO-ANCA+ AAV (P = 7.9 x 10-7, Odds ratio = 3.0 in meta-analysis). The rare allele of the novel disease-associated SNP affected downstream gene expression in primary endothelial cells, specifically.

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

 

Disclosures: None.

 

 

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