| 1. |
- Lindblom, J., et al.
(författare)
-
TRANSCRIPTOME PROFILING AND AUTOIMMUNITY-RELATED SEROLOGICAL MARKERS IDENTIFY TP53 AND C3AR AS DRUG TARGETS IN NEUROPSYCHIATRIC SYSTEMIC LUPUS ERYTHEMATOSUS
- 2022
-
Ingår i: Annals of the Rheumatic Diseases. - : HighWire Press. - 0003-4967 .- 1468-2060. ; 81:Suppl. 1, s. 326-326
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Involvement of the nervous system is a common but poorly understood manifestation of systemic lupus erythematosus (SLE), termed neuropsychiatric SLE (NPSLE). Although studies have reported varying prevalence estimates [1], NPSLE affects at least 20% of patients with SLE within the first years of the disease course [2]. The management of neuropsychiatric SLE (NPSLE) is poorly optimised and specific treatment is lacking.ObjectivesThe aim of this study was to investigate expression quantitative trait loci (eQTLs), the transcriptome, and autoimmunity-related cytokines and autoantibodies in patients with central nervous system (CNS) lupus to gain insights into underlying genetics and biologic mechanisms towards identification of novel drug targets.MethodsWe analysed differentially expressed genes (DEGs), pathways and their druggability via the Drug Gene Interaction database (DGIdb) [3] in active CNS lupus (n=26) versus healthy controls (HC; n=497), and eQTLs in active or past CNS lupus (n=53), based on validated (identified in two independent SLE populations) DEGs in SLE (n=350) versus HC (n=497), in whole blood collected within the frame of the European PRECISESADS consortium [4]. CNS lupus was defined according to SLE Disease Activity Index 2000 (SLEDAI-2K) [5] CNS items or by CNS manifestations such as chorea, acute confusional state, transverse myelitis, aseptic meningitis, and optic neuritis in the absence of predisposing conditions unrelated to SLE. Genome-wide RNA-sequencing and genotyping was previously performed by Illumina assays, and serum levels of 17 cytokines were analysed using a Luminex assay and ELISA [4].ResultsAmong 5631 significant and validated DEGs in active CNS patients compared with HC, 1922 unique DEGs were tagged to 21 and 176 significant KEGG [6] and Reactome [7] pathways, respectively. Pathways included “Interferon signalling”, “TNF signalling” and “Toll-like Receptor Cascades”. The pathways included 29 of 59 DEGs with a |fold change (FC)| > 1.5, 6 genes from 14 significant cis-eQTLs and 10 genes from 22 trans-eQTLs, and 2 genes from 8 cytokines that differed significantly between active CNS lupus and HC. These genes could be targeted by 496 different drugs, with the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and the anti-CD20 B cell depleting monoclonal rituximab with ability to interfere with tumour protein P53 (TP53) activity, and a complement C3a Receptor (C3aR) antagonist being of particular interest.ConclusionIntegrated multilevel omics analysis revealed a set of enriched pathways of potential interest for future drug investigation in CNS lupus, including BTK and C3aR inhibition, and B cell depletion.References[1]Unterman A, Nolte JE, Boaz M, Abady M, Shoenfeld Y, Zandman-Goddard G. Neuropsychiatric syndromes in systemic lupus erythematosus: a meta-analysis. Semin Arthritis Rheum. 2011 Aug; 41(1):1-11[2]Hanly JG, Urowitz MB, Su L, Bae SC, Gordon C, Wallace DJ, et al. Prospective analysis of neuropsychiatric events in an international disease inception cohort of patients with systemic lupus erythematosus. Ann Rheum Dis. 2010 Mar; 69(3):529-535[3]Wagner AH, Coffman AC, Ainscough BJ, Spies NC, Skidmore ZL, Campbell KM, et al. DGIdb 2.0: mining clinically relevant drug-gene interactions. Nucleic Acids Res. 2016 Jan 4; 44(D1):D1036-1044[4]Barturen G, Babaei S, Català-Moll F, Martínez-Bueno M, Makowska Z, Martorell-Marugán J, et al. Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases. Arthritis Rheumatol. 2021 Jun; 73(6):1073-1085[5]Gladman DD, Ibanez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol. 2002 Feb; 29(2):288-291[6]Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K. KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2017 Jan 4; 45(D1):D353-d361[7]Jassal B, Matthews L, Viteri G, Gong C, Lorente P, Fabregat A, et al. The reactome pathway knowledgebase. Nucleic Acids Res. 2020 Jan 8; 48(D1):D498-d503AcknowledgementsThe PRECISESADS clinical consortiumDisclosure of InterestsNone declared
|
|
| 2. |
|
|
| 3. |
- Parodis, Ioannis, 1981-, et al.
(författare)
-
DRUG REPURPOSING FOR TREATING LUPUS NEPHRITIS BASED ON TRANSCRIPTOME PROFILING AND AUTOIMMUNITY-RELATED SEROLOGICAL MARKERS
- 2022
-
Ingår i: Annals of the Rheumatic Diseases. - : HighWire Press. - 0003-4967 .- 1468-2060. ; 81:Suppl. 1, s. 326-326
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Lupus nephritis (LN) is one of the most severe organ manifestations of systemic lupus erythematosus (SLE) and constitutes an important cause of morbidity and death among patients with SLE [1]. The associated renal injury, and ultimately damage, is the result of an immune-mediated process which involves leukocytes, immune complexes, complement and cytokines [2].ObjectivesLupus nephritis (LN) is one of the most severe organ manifestations of systemic lupus erythematosus (SLE) and constitutes an important cause of morbidity and death among patients with SLE [1]. The associated renal injury, and ultimately damage, is the result of an immune-mediated process which involves leukocytes, immune complexes, complement and cytokines [2].MethodsWe analysed differentially expressed genes (DEGs), pathways and their druggability via the Drug Gene Interaction database (DGIdb) [3] in active LN (n=41) versus healthy controls (HC; n=497), and eQTLs in active or past LN (n=87), based on validated (identified in two independent SLE populations) DEGs in SLE (n=350) vs HC (n=497), in whole blood collected within the frame of the European PRECISESADS consortium [4]. Genome-wide RNA-sequencing and genotyping was previously performed by Illumina assays, and serum levels of 17 cytokines and 18 autoantibodies were analysed using a Luminex assay, ELISA, IDS-iSYS and SPAPLUS analyser [4].ResultsA total of 6 869 significant and validated DEGs were identified in active LN patients compared with HC. Of these, 1010 validated DEGs were tagged to 34 KEGG pathways including 24 DEGs with a |fold change (FC)| > 1.5, genes of 18 cis-eQTLs and 3 trans-eQTLs, and 1 gene from cytokines that differed significantly between active LN and HC. Moreover, 2446 validated DEGs were tagged to 216 Reactome pathways included 85 DEGs with a |FC| > 1.5, genes of 21 cis-eQTLs and 5 trans-eQTLs, and 1 gene from cytokines that differed significantly between active LN and HC. These genes could be targeted by 203 different drugs, with the proteasome inhibitor bortezomib interfering with cathepsin B (CTSB) regulation and cyclophosphamide interfering with the regulation of tumour necrosis factor receptor superfamily member 1A (TNFRSF1A) being of particular interest.ConclusionIntegrated multilevel omics analysis in LN revealed a set of enriched pathways of potential interest for future drug investigation. A prospect for proteasome inhibition was implicated.References[1]Croca SC, Rodrigues T, Isenberg DA. Assessment of a lupus nephritis cohort over a 30-year period. Rheumatology (Oxford). 2011 Aug; 50(8):1424-1430.[2]Anders HJ, Saxena R, Zhao MH, Parodis I, Salmon JE, Mohan C. Lupus nephritis. Nat Rev Dis Primers. 2020 Jan 23; 6(1):7.[3]Wagner AH, Coffman AC, Ainscough BJ, Spies NC, Skidmore ZL, Campbell KM, et al. DGIdb 2.0: mining clinically relevant drug-gene interactions. Nucleic Acids Res. 2016 Jan 4; 44(D1):D1036-1044.[4]Barturen G, Babaei S, Català-Moll F, Martínez-Bueno M, Makowska Z, Martorell-Marugán J, et al. Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases. Arthritis Rheumatol. 2021 Jun; 73(6):1073-1085.[5]Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K. KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2017 Jan 4; 45(D1):D353-d361.[6]Jassal B, Matthews L, Viteri G, Gong C, Lorente P, Fabregat A, et al. The reactome pathway knowledgebase. Nucleic Acids Res. 2020 Jan 8; 48(D1):D498-d503.AcknowledgementsThe PRECISESADS Clinical ConsortiumDisclosure of InterestsNone declared
|
|
| 4. |
|
|
