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- Lindblom, Julius, et al.
(författare)
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Distinct gene dysregulation patterns herald precision medicine potentiality in systemic lupus erythematosus
- 2023
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Ingår i: Journal of Autoimmunity. - : Academic Press. - 0896-8411 .- 1095-9157. ; 136
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Parodis, Ioannis, 1981-, et al.
(författare)
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Molecular characterisation of lupus low disease activity state (LLDAS) and DORIS remission by whole-blood transcriptome-based pathways in a pan-European systemic lupus erythematosus cohort
- 2024
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Ingår i: Annals of the Rheumatic Diseases. - : HighWire Press. - 0003-4967 .- 1468-2060.
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To unveil biological milieus underlying low disease activity (LDA) and remission versus active systemic lupus erythematosus (SLE).METHODS: We determined differentially expressed pathways (DEPs) in SLE patients from the PRECISESADS project (NTC02890121) stratified into patients fulfilling and not fulfilling the criteria of (1) Lupus LDA State (LLDAS), (2) Definitions of Remission in SLE remission, and (3) LLDAS exclusive of remission.RESULTS: We analysed data from 321 patients; 40.8% were in LLDAS, and 17.4% in DORIS remission. After exclusion of patients in remission, 28.3% were in LLDAS. Overall, 604 pathways differed significantly in LLDAS versus non-LLDAS patients with an false-discovery rate-corrected p (q)<0.05 and a robust effect size (dr)≥0.36. Accordingly, 288 pathways differed significantly between DORIS remitters and non-remitters (q<0.05 and dr≥0.36). DEPs yielded distinct molecular clusters characterised by differential serological, musculoskeletal, and renal activity. Analysis of partially overlapping samples showed no DEPs between LLDAS and DORIS remission. Drug repurposing potentiality for treating SLE was unveiled, as were important pathways underlying active SLE whose modulation could aid attainment of LLDAS/remission, including toll-like receptor (TLR) cascades, Bruton tyrosine kinase (BTK) activity, the cytotoxic T lymphocyte antigen 4 (CTLA-4)-related inhibitory signalling, and the nucleotide-binding oligomerization domain leucine-rich repeat-containing protein 3 (NLRP3) inflammasome pathway.CONCLUSIONS: We demonstrated for the first time molecular signalling pathways distinguishing LLDAS/remission from active SLE. LLDAS/remission was associated with reversal of biological processes related to SLE pathogenesis and specific clinical manifestations. DEP clustering by remission better grouped patients compared with LLDAS, substantiating remission as the ultimate treatment goal in SLE; however, the lack of substantial pathway differentiation between the two states justifies LLDAS as an acceptable goal from a biological perspective.
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