DRUG REPURPOSING FOR TREATING LUPUS NEPHRITIS BASED ON TRANSCRIPTOME PROFILING AND AUTOIMMUNITY-RELATED SEROLOGICAL MARKERS

• 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

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MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Reumatologi och inflammation (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Rheumatology and Autoimmunity (hsv//eng)

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