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  • Lindblom, JuliusKarolinska Institutet (author)

Distinct gene dysregulation patterns herald precision medicine potentiality in systemic lupus erythematosus

  • Article/chapterEnglish2023

Publisher, publication year, extent ...

  • Academic Press,2023
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:oru-105280
  • https://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-105280URI
  • https://doi.org/10.1016/j.jaut.2023.103025DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:152623638URI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Corrigendum to ‘Distinct gene dysregulation patterns herald precisionmedicine potentiality in systemic lupus erythematosus’ [J. Autoimmun.136 (April 2023) 103025].Julius Lindblom a, Daniel Toro-Domínguez b, Elena Carnero-Montoro b, Lorenzo Beretta c, Maria Orietta Borghi d,e, Jessica Castillo f, Yvonne Enman a, PRECISESADS Clinical Consortium,Chandra Mohan f, Marta E. Alarc ́on-Riquelme b,g, Guillermo Barturen b,h, Ioannis ParoP et al., Journal of Autoimmunity. Volume 140, November 2023, 103052.DOI: 10.1016/j.jaut.2023.103052WOS: 001104353500001PubMed ID: 37142531Scopus: 2-s2.0-85156173183Funding agencies:Professor Nanna Svartz Foundation 202000368Innovative Medicines Initiative (IMI) Joint Undertaking (JU) 115565IMI 2 JU 831434Ulla and Roland Gustafsson Foundation 202126Innovative Medicines Initiative (IMI) Joint Undertaking (JU) 115565IMI 2 JU 831434
  • 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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  • Toro-Domínguez, DanielGENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada / Andalusian Regional Government, Granada, Spain, Medical Genomics, Granada, Spain (author)
  • Carnero-Montoro, ElenaGENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada / Andalusian Regional Government, Granada, Spain, Medical Genomics, Granada, Spain (author)
  • Beretta, LorenzoReferral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Italy (author)
  • Borghi, Maria OriettaDepartment of Clinical Sciences and Community Health, Università Degli Studi di Milano and Istituto Auxologico Italiano, Cusano Milanino Mi, Italy (author)
  • Castillo, JessicaDepartment of Biomedical Engineering, University of Houston, Houston, TX, USA (author)
  • Enman, YvonneKarolinska Institutet (author)
  • Mohan, ChandraDepartment of Biomedical Engineering, University of Houston, Houston, TX, USA (author)
  • Alarcón-Riquelme, Marta E.Karolinska Institutet (author)
  • Barturen, GuillermoGENYO, 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 (author)
  • Parodis, Ioannis,1981-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(Swepub:oru)isps (author)
  • PRECISESADS Clinical Consortium, - (contributor)
  • Karolinska InstitutetGENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada / Andalusian Regional Government, Granada, Spain, Medical Genomics, Granada, Spain (creator_code:org_t)

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  • In:Journal of Autoimmunity: Academic Press1360896-84111095-9157

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