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Molecular pathways in patients with systemic lupus erythematosus revealed by gene-centred DNA sequencing

Sandling, Johanna K. ; Pucholt, Pascal ; Hultin Rosenberg, Lina ; Farias, Fabiana H.G. ; Kozyrev, Sergey V. ; Eloranta, Maija Leena ; Alexsson, Andrei ; Bianchi, Matteo ; Padyukov, Leonid and Bengtsson, Christine LU , et al. (2021) In Annals of the Rheumatic Diseases 80(1). p.109-117
Abstract

Objectives: Systemic lupus erythematosus (SLE) is an autoimmune disease with extensive heterogeneity in disease presentation between patients, which is likely due to an underlying molecular diversity. Here, we aimed at elucidating the genetic aetiology of SLE from the immunity pathway level to the single variant level, and stratify patients with SLE into distinguishable molecular subgroups, which could inform treatment choices in SLE. Methods: We undertook a pathway-centred approach, using sequencing of immunological pathway genes. Altogether 1832 candidate genes were analysed in 958 Swedish patients with SLE and 1026 healthy individuals. Aggregate and single variant association testing was performed, and we generated pathway polygenic... (More)

Objectives: Systemic lupus erythematosus (SLE) is an autoimmune disease with extensive heterogeneity in disease presentation between patients, which is likely due to an underlying molecular diversity. Here, we aimed at elucidating the genetic aetiology of SLE from the immunity pathway level to the single variant level, and stratify patients with SLE into distinguishable molecular subgroups, which could inform treatment choices in SLE. Methods: We undertook a pathway-centred approach, using sequencing of immunological pathway genes. Altogether 1832 candidate genes were analysed in 958 Swedish patients with SLE and 1026 healthy individuals. Aggregate and single variant association testing was performed, and we generated pathway polygenic risk scores (PRS). Results: We identified two main independent pathways involved in SLE susceptibility: T lymphocyte differentiation and innate immunity, characterised by HLA and interferon, respectively. Pathway PRS defined pathways in individual patients, who on average were positive for seven pathways. We found that SLE organ damage was more pronounced in patients positive for the T or B cell receptor signalling pathways. Further, pathway PRS-based clustering allowed stratification of patients into four groups with different risk score profiles. Studying sets of genes with priors for involvement in SLE, we observed an aggregate common variant contribution to SLE at genes previously reported for monogenic SLE as well as at interferonopathy genes. Conclusions: Our results show that pathway risk scores have the potential to stratify patients with SLE beyond clinical manifestations into molecular subsets, which may have implications for clinical follow-up and therapy selection.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
autoimmunity, genetic, lupus erythematosus, polymorphism, systemic
in
Annals of the Rheumatic Diseases
volume
80
issue
1
pages
9 pages
publisher
BMJ Publishing Group
external identifiers
  • pmid:33037003
  • scopus:85096404005
ISSN
0003-4967
DOI
10.1136/annrheumdis-2020-218636
language
English
LU publication?
yes
id
4869e8fd-0422-49b6-8631-d801de373cf9
date added to LUP
2020-12-02 13:35:07
date last changed
2024-09-05 09:11:58
@article{4869e8fd-0422-49b6-8631-d801de373cf9,
  abstract     = {{<p>Objectives: Systemic lupus erythematosus (SLE) is an autoimmune disease with extensive heterogeneity in disease presentation between patients, which is likely due to an underlying molecular diversity. Here, we aimed at elucidating the genetic aetiology of SLE from the immunity pathway level to the single variant level, and stratify patients with SLE into distinguishable molecular subgroups, which could inform treatment choices in SLE. Methods: We undertook a pathway-centred approach, using sequencing of immunological pathway genes. Altogether 1832 candidate genes were analysed in 958 Swedish patients with SLE and 1026 healthy individuals. Aggregate and single variant association testing was performed, and we generated pathway polygenic risk scores (PRS). Results: We identified two main independent pathways involved in SLE susceptibility: T lymphocyte differentiation and innate immunity, characterised by HLA and interferon, respectively. Pathway PRS defined pathways in individual patients, who on average were positive for seven pathways. We found that SLE organ damage was more pronounced in patients positive for the T or B cell receptor signalling pathways. Further, pathway PRS-based clustering allowed stratification of patients into four groups with different risk score profiles. Studying sets of genes with priors for involvement in SLE, we observed an aggregate common variant contribution to SLE at genes previously reported for monogenic SLE as well as at interferonopathy genes. Conclusions: Our results show that pathway risk scores have the potential to stratify patients with SLE beyond clinical manifestations into molecular subsets, which may have implications for clinical follow-up and therapy selection.</p>}},
  author       = {{Sandling, Johanna K. and Pucholt, Pascal and Hultin Rosenberg, Lina and Farias, Fabiana H.G. and Kozyrev, Sergey V. and Eloranta, Maija Leena and Alexsson, Andrei and Bianchi, Matteo and Padyukov, Leonid and Bengtsson, Christine and Jonsson, Roland and Omdal, Roald and Lie, Benedicte A. and Massarenti, Laura and Steffensen, Rudi and Jakobsen, Marianne A. and Lillevang, Søren T. and Lerang, Karoline and Molberg, Øyvind and Voss, Anne and Troldborg, Anne and Jacobsen, Søren and Syvänen, Ann Christine and Jönsen, Andreas and Gunnarsson, Iva and Svenungsson, Elisabet and Rantapää-Dahlqvist, Solbritt and Bengtsson, Anders A. and Sjöwall, Christopher and Leonard, Dag and Lindblad-Toh, Kerstin and Rönnblom, Lars}},
  issn         = {{0003-4967}},
  keywords     = {{autoimmunity; genetic; lupus erythematosus; polymorphism; systemic}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{109--117}},
  publisher    = {{BMJ Publishing Group}},
  series       = {{Annals of the Rheumatic Diseases}},
  title        = {{Molecular pathways in patients with systemic lupus erythematosus revealed by gene-centred DNA sequencing}},
  url          = {{http://dx.doi.org/10.1136/annrheumdis-2020-218636}},
  doi          = {{10.1136/annrheumdis-2020-218636}},
  volume       = {{80}},
  year         = {{2021}},
}