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Stratified Genetic Analysis Reveals Sex Differences In MPO-ANCA-associated Vasculitis

Ekman, Diana ; Sennblad, Bengt ; Knight, Ann ; Karlsson, Åsa ; Rantapää-Dahlqvist, Solbritt ; Berglin, Ewa ; Stegmayr, Bernd ; Baslund, Bo ; Palm, Øyvind and Haukeland, Hilde , et al. (2023) In Rheumatology (Oxford, England) 62(9). p.3213-3218
Abstract

OBJECTIVE: To identify and genetically characterize subgroups of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) based on sex and ANCA subtype.

METHODS: A previously established SNP dataset derived from DNA sequencing of 1853 genes and genotyping of 1088 Scandinavian cases with AAV and 1589 controls was stratified for sex and ANCA subtype and analysed for association with five top AAV SNPs. rs9274619, a lead variant at the HLA-DQB1/HLA-DQA2 locus previously associated with AAV positive for myeloperoxidase (MPO)-ANCA, was analysed for association with the cumulative disease involvement of ten different organ systems.

RESULTS: rs9274619 showed a significantly stronger association to... (More)

OBJECTIVE: To identify and genetically characterize subgroups of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) based on sex and ANCA subtype.

METHODS: A previously established SNP dataset derived from DNA sequencing of 1853 genes and genotyping of 1088 Scandinavian cases with AAV and 1589 controls was stratified for sex and ANCA subtype and analysed for association with five top AAV SNPs. rs9274619, a lead variant at the HLA-DQB1/HLA-DQA2 locus previously associated with AAV positive for myeloperoxidase (MPO)-ANCA, was analysed for association with the cumulative disease involvement of ten different organ systems.

RESULTS: rs9274619 showed a significantly stronger association to MPO-ANCA positive females than males (P = 2.0 x 1 0 -4, OR = 2.3 (95%CI 1.5-3.5), whereas proteinase 3 (PR3)-ANCA-associated variants rs1042335, rs9277341 (HLA-DPB1/A1) and rs28929474 (SERPINA1) were equally associated with females and males with PR3-ANCA. In MPO-ANCA positive cases, carriers of the rs9274619 risk allele were more prone to disease engagement of eyes (P = 0.021, OR = 11 (95%CI 2.2-205)) but less prone to pulmonary involvement (P = 0.026, OR = 0.52 (95%CI 0.30-0.92)). Moreover, AAV with both MPO-ANCA and PR3-ANCA was associated with the PR3-ANCA lead SNP rs1042335 (P = 0.0015, OR = 0.091 (95%CI 0.0022-0.55)) but not with rs9274619.

CONCLUSIONS: Females and males with MPO-ANCA positive AAV differ in genetic predisposition to disease, suggesting at least partially distinct disease mechanisms between the sexes. Double ANCA-positive AAV cases are genetically similar to PR3-ANCA positive cases, providing clues to the clinical follow-up and treatment of these patients.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Rheumatology (Oxford, England)
volume
62
issue
9
pages
3213 - 3218
publisher
Oxford University Press
external identifiers
  • pmid:37004177
  • scopus:85171998269
ISSN
1462-0332
DOI
10.1093/rheumatology/kead152
language
English
LU publication?
yes
additional info
© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.
id
88d8db9e-83c3-46e9-84bd-f4d8b43683fa
date added to LUP
2023-05-05 16:08:46
date last changed
2024-07-12 08:17:31
@article{88d8db9e-83c3-46e9-84bd-f4d8b43683fa,
  abstract     = {{<p>OBJECTIVE: To identify and genetically characterize subgroups of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) based on sex and ANCA subtype.</p><p>METHODS: A previously established SNP dataset derived from DNA sequencing of 1853 genes and genotyping of 1088 Scandinavian cases with AAV and 1589 controls was stratified for sex and ANCA subtype and analysed for association with five top AAV SNPs. rs9274619, a lead variant at the HLA-DQB1/HLA-DQA2 locus previously associated with AAV positive for myeloperoxidase (MPO)-ANCA, was analysed for association with the cumulative disease involvement of ten different organ systems.</p><p>RESULTS: rs9274619 showed a significantly stronger association to MPO-ANCA positive females than males (P = 2.0 x 1 0 -4, OR = 2.3 (95%CI 1.5-3.5), whereas proteinase 3 (PR3)-ANCA-associated variants rs1042335, rs9277341 (HLA-DPB1/A1) and rs28929474 (SERPINA1) were equally associated with females and males with PR3-ANCA. In MPO-ANCA positive cases, carriers of the rs9274619 risk allele were more prone to disease engagement of eyes (P = 0.021, OR = 11 (95%CI 2.2-205)) but less prone to pulmonary involvement (P = 0.026, OR = 0.52 (95%CI 0.30-0.92)). Moreover, AAV with both MPO-ANCA and PR3-ANCA was associated with the PR3-ANCA lead SNP rs1042335 (P = 0.0015, OR = 0.091 (95%CI 0.0022-0.55)) but not with rs9274619.</p><p>CONCLUSIONS: Females and males with MPO-ANCA positive AAV differ in genetic predisposition to disease, suggesting at least partially distinct disease mechanisms between the sexes. Double ANCA-positive AAV cases are genetically similar to PR3-ANCA positive cases, providing clues to the clinical follow-up and treatment of these patients.</p>}},
  author       = {{Ekman, Diana and Sennblad, Bengt and Knight, Ann and Karlsson, Åsa 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 Omdal, Roald and Jonsson, Roland and Rönnblom, Lars and Eriksson, Per and Lindblad-Toh, Kerstin and Dahlqvist, Johanna}},
  issn         = {{1462-0332}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{9}},
  pages        = {{3213--3218}},
  publisher    = {{Oxford University Press}},
  series       = {{Rheumatology (Oxford, England)}},
  title        = {{Stratified Genetic Analysis Reveals Sex Differences In MPO-ANCA-associated Vasculitis}},
  url          = {{http://dx.doi.org/10.1093/rheumatology/kead152}},
  doi          = {{10.1093/rheumatology/kead152}},
  volume       = {{62}},
  year         = {{2023}},
}