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

Dahlqvist, Johanna ; Ekman, Diana ; Sennblad, Bengt ; Kozyrev, Sergey V ; Nordin, Jessika ; Karlsson, Åsa ; Meadows, Jennifer R S ; Hellbacher, Erik ; Rantapää-Dahlqvist, Solbritt and Berglin, Ewa , et al. (2022) In Rheumatology (Oxford, England) 61(8). p.3461-3470
Abstract

OBJECTIVE: To identify and characterize genetic loci associated with the risk of developing anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV).

METHODS: 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.

RESULTS: Proteinase 3 ANCA positive (PR3-ANCA+) AAV was significantly associated with two independent loci in the HLA-DPB1/A1 region (rs1042335, p= 6.3... (More)

OBJECTIVE: To identify and characterize genetic loci associated with the risk of developing anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV).

METHODS: 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.

RESULTS: 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.

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Rheumatology (Oxford, England)
volume
61
issue
8
pages
3461 - 3470
publisher
Oxford University Press
external identifiers
  • pmid:34888651
  • scopus:85138148342
ISSN
1462-0332
DOI
10.1093/rheumatology/keab912
language
English
LU publication?
yes
additional info
© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.
id
9eff6e3d-c4ed-4003-a6ce-37f03928a7fa
date added to LUP
2021-12-16 09:19:52
date last changed
2025-03-23 04:24:52
@article{9eff6e3d-c4ed-4003-a6ce-37f03928a7fa,
  abstract     = {{<p>OBJECTIVE: To identify and characterize genetic loci associated with the risk of developing anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV).</p><p>METHODS: 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.</p><p>RESULTS: 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.</p><p>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.</p>}},
  author       = {{Dahlqvist, Johanna and Ekman, Diana and Sennblad, Bengt and Kozyrev, Sergey V and Nordin, Jessika and Karlsson, Åsa and Meadows, Jennifer R S and Hellbacher, Erik and Rantapää-Dahlqvist, Solbritt and Berglin, Ewa and Stegmayr, Bernd and Baslund, Bo and Palm, Øyvind and Haukeland, Hilde and Gunnarsson, Iva and Bruchfeld, Annette and Segelmark, Mårten and Ohlsson, Sophie and Mohammad, Aladdin J and Svärd, Anna and Pullerits, Rille and Herlitz, Hans and Söderbergh, Annika and Rosengren Pielberg, Gerli and Hultin Rosenberg, Lina and Bianchi, Matteo and Murén, Eva and Omdal, Roald and Jonsson, Roland and Eloranta, Maija-Leena and Rönnblom, Lars and Söderkvist, Peter and Knight, Ann and Eriksson, Per and Lindblad-Toh, Kerstin}},
  issn         = {{1462-0332}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{3461--3470}},
  publisher    = {{Oxford University Press}},
  series       = {{Rheumatology (Oxford, England)}},
  title        = {{Identification and Functional Characterization of a Novel Susceptibility Locus for Small Vessel Vasculitis with MPO-ANCA}},
  url          = {{http://dx.doi.org/10.1093/rheumatology/keab912}},
  doi          = {{10.1093/rheumatology/keab912}},
  volume       = {{61}},
  year         = {{2022}},
}