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Unraveling the Genetics of Shared Clinical and Serological Manifestations in Patients With Systemic Inflammatory Autoimmune Diseases

Bianchi, Matteo ; Kozyrev, Sergey V ; Notarnicola, Antonella ; Sandling, Johanna K ; Pettersson, Mats ; Leonard, Dag ; Sjöwall, Christopher ; Gunnarsson, Iva ; Rantapää-Dahlqvist, Solbritt and Bengtsson, Anders A LU , et al. (2024) In Arthritis & Rheumatology
Abstract

OBJECTIVE: Systemic inflammatory autoimmune diseases (SIADs) such as systemic lupus erythematosus (SLE), primary Sjögren disease (pSS), and idiopathic inflammatory myopathies (myositis) are complex conditions characterized by shared circulating autoantibodies and clinical manifestations, including skin rashes, among others. This study was aimed at elucidating the genetics underlying these common features.

METHODS: We performed targeted DNA sequencing of coding and regulatory regions from approximately 1,900 immune-related genes in a large cohort of 2,292 well-characterized Scandinavian patients with SIADs with SLE, pSS, and myositis as well as 1,252 controls. A gene-based functionally weighted genetic score for aggregate testing... (More)

OBJECTIVE: Systemic inflammatory autoimmune diseases (SIADs) such as systemic lupus erythematosus (SLE), primary Sjögren disease (pSS), and idiopathic inflammatory myopathies (myositis) are complex conditions characterized by shared circulating autoantibodies and clinical manifestations, including skin rashes, among others. This study was aimed at elucidating the genetics underlying these common features.

METHODS: We performed targeted DNA sequencing of coding and regulatory regions from approximately 1,900 immune-related genes in a large cohort of 2,292 well-characterized Scandinavian patients with SIADs with SLE, pSS, and myositis as well as 1,252 controls. A gene-based functionally weighted genetic score for aggregate testing of all genetic variants, including rare variants, was complemented by in silico functional analyses and in vitro reporter experiments.

RESULTS: Case-control association analysis detected known and potentially novel genetic loci in agreement with previous genetic and transcriptomics findings linked to the SIAD autoimmune background. Intriguingly, case-case comparisons between patient subgroups with and without specific autoantibodies revealed that the subgroups defined by antinuclear antibodies and anti-double-stranded DNA antibodies have unique genetic profiles reflecting their heterogeneity. When focusing on clinical features, we overall showed that dual-specificity phosphatase 1 (DUSP1) protective genetic variants lead to increased gene expression and potentially to anti-inflammatory effects on the SIAD-associated skin phenotype. This is consistent with recent genetic findings on eczema and with the previously reported down-regulation of the MAPK signaling-related gene DUSP1 in other skin disorders.

CONCLUSION: Together, this suggests common molecular mechanisms potentially underlying overlapping clinical manifestations shared among different disorders and informs clinical heterogeneity, which could be translated to improve disease diagnostic and treatment, also in more generalized disease frameworks.

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organization
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type
Contribution to journal
publication status
epub
subject
in
Arthritis & Rheumatology
publisher
John Wiley & Sons Inc.
external identifiers
  • pmid:39284741
  • scopus:85205879351
ISSN
2326-5205
DOI
10.1002/art.42988
language
English
LU publication?
yes
additional info
© 2024 The Author(s). Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.
id
13b3a836-7720-4bc2-aa37-9874b12fd5f4
date added to LUP
2025-01-23 12:28:25
date last changed
2025-07-11 17:48:40
@article{13b3a836-7720-4bc2-aa37-9874b12fd5f4,
  abstract     = {{<p>OBJECTIVE: Systemic inflammatory autoimmune diseases (SIADs) such as systemic lupus erythematosus (SLE), primary Sjögren disease (pSS), and idiopathic inflammatory myopathies (myositis) are complex conditions characterized by shared circulating autoantibodies and clinical manifestations, including skin rashes, among others. This study was aimed at elucidating the genetics underlying these common features.</p><p>METHODS: We performed targeted DNA sequencing of coding and regulatory regions from approximately 1,900 immune-related genes in a large cohort of 2,292 well-characterized Scandinavian patients with SIADs with SLE, pSS, and myositis as well as 1,252 controls. A gene-based functionally weighted genetic score for aggregate testing of all genetic variants, including rare variants, was complemented by in silico functional analyses and in vitro reporter experiments.</p><p>RESULTS: Case-control association analysis detected known and potentially novel genetic loci in agreement with previous genetic and transcriptomics findings linked to the SIAD autoimmune background. Intriguingly, case-case comparisons between patient subgroups with and without specific autoantibodies revealed that the subgroups defined by antinuclear antibodies and anti-double-stranded DNA antibodies have unique genetic profiles reflecting their heterogeneity. When focusing on clinical features, we overall showed that dual-specificity phosphatase 1 (DUSP1) protective genetic variants lead to increased gene expression and potentially to anti-inflammatory effects on the SIAD-associated skin phenotype. This is consistent with recent genetic findings on eczema and with the previously reported down-regulation of the MAPK signaling-related gene DUSP1 in other skin disorders.</p><p>CONCLUSION: Together, this suggests common molecular mechanisms potentially underlying overlapping clinical manifestations shared among different disorders and informs clinical heterogeneity, which could be translated to improve disease diagnostic and treatment, also in more generalized disease frameworks.</p>}},
  author       = {{Bianchi, Matteo and Kozyrev, Sergey V and Notarnicola, Antonella and Sandling, Johanna K and Pettersson, Mats and Leonard, Dag and Sjöwall, Christopher and Gunnarsson, Iva and Rantapää-Dahlqvist, Solbritt and Bengtsson, Anders A and Jönsen, Andreas and Svenungsson, Elisabet and Enocsson, Helena and Kvarnström, Marika and Forsblad-d'Elia, Helena and Bucher, Sara Magnusson and Norheim, Katrine B and Baecklund, Eva and Jonsson, Roland and Hammenfors, Daniel and Eriksson, Per and Mandl, Thomas and Omdal, Roald and Padyukov, Leonid and Andersson, Helena and Molberg, Øyvind and Diederichsen, Louise Pyndt and Syvänen, Ann-Christine and Wahren-Herlenius, Marie and Nordmark, Gunnel and Lundberg, Ingrid E and Rönnblom, Lars and Lindblad-Toh, Kerstin}},
  issn         = {{2326-5205}},
  language     = {{eng}},
  month        = {{09}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Arthritis & Rheumatology}},
  title        = {{Unraveling the Genetics of Shared Clinical and Serological Manifestations in Patients With Systemic Inflammatory Autoimmune Diseases}},
  url          = {{http://dx.doi.org/10.1002/art.42988}},
  doi          = {{10.1002/art.42988}},
  year         = {{2024}},
}