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Region Hovedstaden - en del af Københavns Universitetshospital
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Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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  • Johanna Dahlqvist
  • Diana Ekman
  • Bengt Sennblad
  • Sergey V Kozyrev
  • Jessika Nordin
  • Åsa Karlsson
  • Jennifer R S Meadows
  • Erik Hellbacher
  • Solbritt Rantapää-Dahlqvist
  • Ewa Berglin
  • Bernd Stegmayr
  • Bo Baslund
  • Øyvind Palm
  • Hilde Haukeland
  • Iva Gunnarsson
  • Annette Bruchfeld
  • Mårten Segelmark
  • Sophie Ohlsson
  • Aladdin J Mohammad
  • Anna Svärd
  • Rille Pullerits
  • Hans Herlitz
  • Annika Söderbergh
  • Gerli Rosengren Pielberg
  • Lina Hultin Rosenberg
  • Matteo Bianchi
  • Eva Murén
  • Roald Omdal
  • Roland Jonsson
  • Maija-Leena Eloranta
  • Lars Rönnblom
  • Peter Söderkvist
  • Ann Knight
  • Per Eriksson
  • Kerstin Lindblad-Toh
Vis graf over relationer

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.

OriginalsprogEngelsk
TidsskriftRheumatology (Oxford, England)
Vol/bind61
Udgave nummer8
Sider (fra-til)3461-3470
Antal sider10
ISSN1462-0324
DOI
StatusUdgivet - 3 aug. 2022

Bibliografisk note

© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.

ID: 80464792