Ioannis Parodis1, Julius Lindblom1, Daniel Toro-Domínguez2, Elena Carnero-Montoro2, Maria Orietta Borghi3, Jessica Castillo4, Yvonne Enman5, Chandra Mohan4, Marta Alarcon-Riquelme2 and Guillermo Barturen2, 1Karolinska Institutet, Stockholm, Sweden, 2Center for Genomics and Oncological Research (GENYO), Granada, Spain, 3Università degli Studi di Milano and Istituto Auxologico Italiano, Milano, Italy, 4University of Houston, Houston, TX, 5Karolinska Institutet, Sundbyberg, Sweden
Background/Purpose: LN is one of the most severe organ manifestations of SLE and constitutes an important cause of morbidity and death among patients with SLE (Croca et al. 2011). The associated renal injury, and ultimately damage, is the result of an immune-mediated process which involves leukocytes, immune complexes, complement and cytokines (Anders et al. 2020). We investigated expression quantitative trait loci (eQTLs), the transcriptome and autoimmunity-related cytokines and autoantibodies in patients with active and/or past LN to gain insights into pathogenesis and identify drug targets.
Methods: We analysed differentially expressed genes (DEGs), pathways and their druggability via the Drug Gene Interaction database (DGIdb) (Wagner et al. 2016) 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 (Barturen et al. 2021). All patients with SLE were diagnosed according to the ACR classification criteria (Hochberg et al. 1997). 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 (Barturen et al. 2021).
Results: A total of 6869 significant and validated DEGs were identified in active LN patients compared with HC. Of those, 2692 DEGs contributed to 34 dysregulated KEGG (Kanehisa et al. 2017) pathways and 216 Reactome (Jassal et al. 2020) pathways, including the Fc gamma Receptor-mediated phagocytosis, TNF signalling pathway, and leukocyte transendothelial migration. Pathways included 24 of 203 DEGs with a fold change < 0.66 or >1.5, 18 genes from 76 significant cis-eQTLs and 3 genes from 18 trans-eQTLs, and 1 gene from 6 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.
Conclusion: Integrated multilevel omics analysis in LN revealed a set of enriched pathways of potential interest for future drug investigation in LN, with implications for proteasome inhibition.
Disclosures: I. Parodis, GlaxoSmithKlein(GSK), Amgen, AstraZeneca, Aurinia Pharmaceuticals, Eli Lilly, Gilead, Janssen, Novartis, Roche; J. Lindblom, None; D. Toro-Domínguez, None; E. Carnero-Montoro, None; M. Borghi, None; J. Castillo, None; Y. Enman, None; C. Mohan, None; M. Alarcon-Riquelme, None; G. Barturen, None.
