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Genetic risk factors and clinical manifestations of systemic lupus erythematosus : Large-scale analysis of genetic predisposition and disease subtypes

Reid, Sarah ; Sandling, Johanna K. ; Pucholt, Pascal ; Sayadi, Ahmed ; Frodlund, Martina ; Lerang, Karoline ; Gunnarsson, Iva ; Jönsen, Andreas LU ; Syvänen, Ann Christine and Molberg, Øyvind , et al. (2026) In Journal of Internal Medicine 299(1). p.95-108
Abstract

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease with a heterogenous clinical picture. This study aimed to link genetic SLE predisposition with relevant clinical manifestations. Method: Datasets best corresponding to the 11 American College of Rheumatology 1982 (ACR-82) classification criteria for SLE in a large, public database (FinnGen consortium, >218,000 individuals) were identified. Mendelian randomization analysis was conducted to evaluate the effect of a high genetic SLE predisposition on each manifestation. Next, validation was conducted in a clinical SLE cohort comprising 1487 genotyped Scandinavian patients with detailed clinical data. Based on the public datasets, genetic risk scores (GRSs) for each... (More)

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease with a heterogenous clinical picture. This study aimed to link genetic SLE predisposition with relevant clinical manifestations. Method: Datasets best corresponding to the 11 American College of Rheumatology 1982 (ACR-82) classification criteria for SLE in a large, public database (FinnGen consortium, >218,000 individuals) were identified. Mendelian randomization analysis was conducted to evaluate the effect of a high genetic SLE predisposition on each manifestation. Next, validation was conducted in a clinical SLE cohort comprising 1487 genotyped Scandinavian patients with detailed clinical data. Based on the public datasets, genetic risk scores (GRSs) for each relevant manifestation were constructed for each patient. Associations between each GRS and the corresponding ACR-82 criterion were evaluated using logistic regression. Results: In the FinnGen biobank, the cumulative effect of the 57 SLE risk SNPs was associated with an increased risk of rosacea, OR 1.09 (1.03–1.16), polyarthropathies, OR 1.10 (1.06–1.14), pleural effusions, OR 1.09 (1.04–1.14), and hemolytic anemia, OR 1.32 (1.10–1.58). In the clinical cohort, 5 of the 11 GRSs generated from the public datasets were associated with their corresponding ACR-82 criterion: arthritis, OR 1.15 (1.02–1.31), renal disorder, OR 1.15 (1.04–1.29), neurologic disorder, OR 1.24 (1.04–1.47), hematologic disorder, OR 1.12 (1.00–1.24), and immunologic disorder, OR 1.37 (1.22–1.56). Conclusion: The findings demonstrate that known SLE risk gene variants play a role in the development of at least half of the ACR-82 criteria for SLE, indicating a future possibility of using genetics to predict a variety of disease sub-phenotypes in SLE.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
autoimmunity, disease subtypes, FinnGen consortium, genetic risk score, Mendelian randomization, systemic lupus erythematosus
in
Journal of Internal Medicine
volume
299
issue
1
pages
14 pages
publisher
Wiley-Blackwell
external identifiers
  • pmid:41200769
  • scopus:105021376740
ISSN
0954-6820
DOI
10.1111/joim.70040
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2025 The Author(s). Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.
id
7b161fe1-dd84-4798-9639-51507aaf9c2e
date added to LUP
2025-12-19 14:06:03
date last changed
2026-01-02 15:38:31
@article{7b161fe1-dd84-4798-9639-51507aaf9c2e,
  abstract     = {{<p>Background: Systemic lupus erythematosus (SLE) is an autoimmune disease with a heterogenous clinical picture. This study aimed to link genetic SLE predisposition with relevant clinical manifestations. Method: Datasets best corresponding to the 11 American College of Rheumatology 1982 (ACR-82) classification criteria for SLE in a large, public database (FinnGen consortium, &gt;218,000 individuals) were identified. Mendelian randomization analysis was conducted to evaluate the effect of a high genetic SLE predisposition on each manifestation. Next, validation was conducted in a clinical SLE cohort comprising 1487 genotyped Scandinavian patients with detailed clinical data. Based on the public datasets, genetic risk scores (GRSs) for each relevant manifestation were constructed for each patient. Associations between each GRS and the corresponding ACR-82 criterion were evaluated using logistic regression. Results: In the FinnGen biobank, the cumulative effect of the 57 SLE risk SNPs was associated with an increased risk of rosacea, OR 1.09 (1.03–1.16), polyarthropathies, OR 1.10 (1.06–1.14), pleural effusions, OR 1.09 (1.04–1.14), and hemolytic anemia, OR 1.32 (1.10–1.58). In the clinical cohort, 5 of the 11 GRSs generated from the public datasets were associated with their corresponding ACR-82 criterion: arthritis, OR 1.15 (1.02–1.31), renal disorder, OR 1.15 (1.04–1.29), neurologic disorder, OR 1.24 (1.04–1.47), hematologic disorder, OR 1.12 (1.00–1.24), and immunologic disorder, OR 1.37 (1.22–1.56). Conclusion: The findings demonstrate that known SLE risk gene variants play a role in the development of at least half of the ACR-82 criteria for SLE, indicating a future possibility of using genetics to predict a variety of disease sub-phenotypes in SLE.</p>}},
  author       = {{Reid, Sarah and Sandling, Johanna K. and Pucholt, Pascal and Sayadi, Ahmed and Frodlund, Martina and Lerang, Karoline and Gunnarsson, Iva and Jönsen, Andreas and Syvänen, Ann Christine and Molberg, Øyvind and Rantapää-Dahlqvist, Solbritt and Rudin, Anna and Sjöwall, Christopher and Svenungsson, Elisabet and Bengtsson, Anders A. and Rönnblom, Lars and Leonard, Dag}},
  issn         = {{0954-6820}},
  keywords     = {{autoimmunity; disease subtypes; FinnGen consortium; genetic risk score; Mendelian randomization; systemic lupus erythematosus}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{95--108}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Journal of Internal Medicine}},
  title        = {{Genetic risk factors and clinical manifestations of systemic lupus erythematosus : Large-scale analysis of genetic predisposition and disease subtypes}},
  url          = {{http://dx.doi.org/10.1111/joim.70040}},
  doi          = {{10.1111/joim.70040}},
  volume       = {{299}},
  year         = {{2026}},
}