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The HLA region in ANCA-associated vasculitis : characterisation of genetic associations in a Scandinavian patient population

Lundtoft, Christian ; Knight, Ann ; Meadows, Jennifer R S ; Karlsson, Åsa ; Rantapää-Dahlqvist, Solbritt ; Berglin, Ewa ; Palm, Øyvind ; Haukeland, Hilde ; Gunnarsson, Iva and Bruchfeld, Annette , et al. (2024) In RMD Open 10(2). p.1-10
Abstract

OBJECTIVE: The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are inflammatory disorders with ANCA autoantibodies recognising either proteinase 3 (PR3-AAV) or myeloperoxidase (MPO-AAV). PR3-AAV and MPO-AAV have been associated with distinct loci in the human leucocyte antigen (HLA) region. While the association between MPO-AAV and HLA has been well characterised in East Asian populations where MPO-AAV is more common, studies in populations of European descent are limited. The aim of this study was to thoroughly characterise associations to the HLA region in Scandinavian patients with PR3-AAV as well as MPO-AAV.

METHODS: Genotypes of single-nucleotide polymorphisms (SNPs) located in the HLA region were... (More)

OBJECTIVE: The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are inflammatory disorders with ANCA autoantibodies recognising either proteinase 3 (PR3-AAV) or myeloperoxidase (MPO-AAV). PR3-AAV and MPO-AAV have been associated with distinct loci in the human leucocyte antigen (HLA) region. While the association between MPO-AAV and HLA has been well characterised in East Asian populations where MPO-AAV is more common, studies in populations of European descent are limited. The aim of this study was to thoroughly characterise associations to the HLA region in Scandinavian patients with PR3-AAV as well as MPO-AAV.

METHODS: Genotypes of single-nucleotide polymorphisms (SNPs) located in the HLA region were extracted from a targeted exome-sequencing dataset comprising Scandinavian AAV cases and controls. Classical HLA alleles were called using xHLA. After quality control, association analyses were performed of a joint SNP/classical HLA allele dataset for cases with PR3-AAV (n=411) and MPO-AAV (n=162) versus controls (n=1595). Disease-associated genetic variants were analysed for association with organ involvement, age at diagnosis and relapse, respectively.

RESULTS: PR3-AAV was significantly associated with both HLA-DPB1*04:01 and rs1042335 at the
HLA-DPB1 locus, also after stepwise conditional analysis. MPO-AAV was significantly associated with HLA-DRB1*04:04. Neither carriage of HLA-DPB1*04:01 alleles in PR3-AAV nor of HLA-DRB1*04:04 alleles in MPO-AAV were associated with organ involvement, age at diagnosis or relapse.

CONCLUSIONS: The association to the HLA region was distinct in Scandinavian cases with MPO-AAV compared with cases of East Asian descent. In PR3-AAV, the two separate signals of association to the
HLD-DPB1 region mediate potentially different functional effects.

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type
Contribution to journal
publication status
published
subject
keywords
Humans, Antibodies, Antineutrophil Cytoplasmic/genetics, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/genetics, Myeloblastin/genetics, Genotype, Recurrence
in
RMD Open
volume
10
issue
2
pages
1 - 10
publisher
BMJ Publishing Group
external identifiers
  • scopus:85190319194
  • pmid:38580345
ISSN
2056-5933
DOI
10.1136/rmdopen-2023-004039
language
English
LU publication?
yes
additional info
© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
id
1f8ed40c-1c73-4acf-b83a-6c2652bb4bd0
date added to LUP
2024-04-15 18:15:19
date last changed
2024-04-29 08:46:15
@article{1f8ed40c-1c73-4acf-b83a-6c2652bb4bd0,
  abstract     = {{<p>OBJECTIVE: The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are inflammatory disorders with ANCA autoantibodies recognising either proteinase 3 (PR3-AAV) or myeloperoxidase (MPO-AAV). PR3-AAV and MPO-AAV have been associated with distinct loci in the human leucocyte antigen (HLA) region. While the association between MPO-AAV and HLA has been well characterised in East Asian populations where MPO-AAV is more common, studies in populations of European descent are limited. The aim of this study was to thoroughly characterise associations to the HLA region in Scandinavian patients with PR3-AAV as well as MPO-AAV.</p><p>METHODS: Genotypes of single-nucleotide polymorphisms (SNPs) located in the HLA region were extracted from a targeted exome-sequencing dataset comprising Scandinavian AAV cases and controls. Classical HLA alleles were called using xHLA. After quality control, association analyses were performed of a joint SNP/classical HLA allele dataset for cases with PR3-AAV (n=411) and MPO-AAV (n=162) versus controls (n=1595). Disease-associated genetic variants were analysed for association with organ involvement, age at diagnosis and relapse, respectively.</p><p>RESULTS: PR3-AAV was significantly associated with both HLA-DPB1*04:01 and rs1042335 at the <br>
 HLA-DPB1 locus, also after stepwise conditional analysis. MPO-AAV was significantly associated with HLA-DRB1*04:04. Neither carriage of HLA-DPB1*04:01 alleles in PR3-AAV nor of HLA-DRB1*04:04 alleles in MPO-AAV were associated with organ involvement, age at diagnosis or relapse.<br>
 </p><p>CONCLUSIONS: The association to the HLA region was distinct in Scandinavian cases with MPO-AAV compared with cases of East Asian descent. In PR3-AAV, the two separate signals of association to the <br>
 HLD-DPB1 region mediate potentially different functional effects.<br>
 </p>}},
  author       = {{Lundtoft, Christian and Knight, Ann and Meadows, Jennifer R S and Karlsson, Åsa and Rantapää-Dahlqvist, Solbritt and Berglin, Ewa and Palm, Øyvind and Haukeland, Hilde and Gunnarsson, Iva and Bruchfeld, Annette and Segelmark, Mårten and Ohlsson, Sophie and Mohammad, Aladdin J and Eriksson, Per and Söderkvist, Peter and Ronnblom, Lars and Omdal, Roald and Jonsson, Roland and Lindblad-Toh, Kerstin and Dahlqvist, Johanna}},
  issn         = {{2056-5933}},
  keywords     = {{Humans; Antibodies, Antineutrophil Cytoplasmic/genetics; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/genetics; Myeloblastin/genetics; Genotype; Recurrence}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{2}},
  pages        = {{1--10}},
  publisher    = {{BMJ Publishing Group}},
  series       = {{RMD Open}},
  title        = {{The HLA region in ANCA-associated vasculitis : characterisation of genetic associations in a Scandinavian patient population}},
  url          = {{http://dx.doi.org/10.1136/rmdopen-2023-004039}},
  doi          = {{10.1136/rmdopen-2023-004039}},
  volume       = {{10}},
  year         = {{2024}},
}