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Distinct gene dysre...
Distinct gene dysregulation patterns herald precision medicine potentiality in systemic lupus erythematosus
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- Lindblom, Julius (författare)
- Karolinska Institutet
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- Toro-Domínguez, Daniel (författare)
- GENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada / Andalusian Regional Government, Granada, Spain, Medical Genomics, Granada, Spain
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- Carnero-Montoro, Elena (författare)
- GENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada / Andalusian Regional Government, Granada, Spain, Medical Genomics, Granada, Spain
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- Beretta, Lorenzo (författare)
- Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Italy
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- Borghi, Maria Orietta (författare)
- Department of Clinical Sciences and Community Health, Università Degli Studi di Milano and Istituto Auxologico Italiano, Cusano Milanino Mi, Italy
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- Castillo, Jessica (författare)
- Department of Biomedical Engineering, University of Houston, Houston, TX, USA
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- Enman, Yvonne (författare)
- Karolinska Institutet
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- Mohan, Chandra (författare)
- Department of Biomedical Engineering, University of Houston, Houston, TX, USA
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- Alarcón-Riquelme, Marta E. (författare)
- Karolinska Institutet
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- Barturen, Guillermo (författare)
- GENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada / Andalusian Regional Government, Granada, Spain, Medical Genomics, Granada, Spain; Department of Genetics, Faculty of Sciences, University of Granada, Granada, Spain
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- Parodis, Ioannis, 1981- (författare)
- Karolinska Institutet,Örebro universitet,Institutionen för medicinska vetenskaper,Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Department of Rheumatology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
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PRECISESADS Clinical Consortium, - (bidragsgivare)
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(creator_code:org_t)
- Academic Press, 2023
- 2023
- Engelska.
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Ingår i: Journal of Autoimmunity. - : Academic Press. - 0896-8411 .- 1095-9157. ; 136
- Relaterad länk:
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- OBJECTIVES: We aimed at investigating the whole-blood transcriptome, expression quantitative trait loci (eQTLs), and levels of selected serological markers in patients with SLE versus healthy controls (HC) to gain insight into pathogenesis and identify drug targets.METHODS: We analyzed differentially expressed genes (DEGs) and dysregulated gene modules in a cohort of 350 SLE patients and 497 HC from the European PRECISESADS project (NTC02890121), split into a discovery (60%) and a replication (40%) set. Replicated DEGs qualified for eQTL, pathway enrichment, regulatory network, and druggability analysis. For validation purposes, a separate gene module analysis was performed in an independent cohort (GSE88887).RESULTS: Analysis of 521 replicated DEGs identified multiple enriched interferon signaling pathways through Reactome. Gene module analysis yielded 18 replicated gene modules in SLE patients, including 11 gene modules that were validated in GSE88887. Three distinct gene module clusters were defined i.e., "interferon/plasma cells", "inflammation", and "lymphocyte signaling". Predominant downregulation of the lymphocyte signaling cluster denoted renal activity. By contrast, upregulation of interferon-related genes indicated hematological activity and vasculitis. Druggability analysis revealed several potential drugs interfering with dysregulated genes within the "interferon" and "PLK1 signaling events" modules. STAT1 was identified as the chief regulator in the most enriched signaling molecule network. Drugs annotated to 15 DEGs associated with cis-eQTLs included bortezomib for its ability to modulate CTSL activity. Belimumab was annotated to TNFSF13B (BAFF) and daratumumab was annotated to CD38 among the remaining replicated DEGs.CONCLUSIONS: Modulation of interferon, STAT1, PLK1, B and plasma cell signatures showed promise as viable approaches to treat SLE, pointing to their importance in SLE pathogenesis.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Reumatologi och inflammation (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Rheumatology and Autoimmunity (hsv//eng)
Nyckelord
- Autoimmunity
- Biomarkers
- Drug repurposing
- Systemic lupus erythematosus
- Systems biology
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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- Av författaren/redakt...
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Lindblom, Julius
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Toro-Domínguez, ...
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Carnero-Montoro, ...
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Beretta, Lorenzo
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Borghi, Maria Or ...
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Castillo, Jessic ...
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Enman, Yvonne
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Mohan, Chandra
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Alarcón-Riquelme ...
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Barturen, Guille ...
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Parodis, Ioannis ...
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PRECISESADS Clin ...
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- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Reumatologi och ...
- Artiklar i publikationen
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Journal of Autoi ...
- Av lärosätet
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Örebro universitet
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Karolinska Institutet