WCN25-468 CLINICAL PROFILE OF ANTI-GBM NEPHRITIS IN CHILDREN AND THE FACTORS ASSOCIATED WITH ADVERSE LONG-TERM OUTCOMES

Introduction: Effective treatment for acute kidney disease (AKI) is currently not available.Mendelian randomization (MR) approach has been widely used to discover novel therapeutic targets, and here we conducted a systematic druggable genome-wide MR to explore the therapeutic targets for AKI.Methods: We firstly acquired druggable genes of blood expression quantitative trait loci (eQTLs), and conducted a comprehensive analysis to assess the causal relationship of targets on AKI involving two-sample Mendelian randomization (MR, for mRNA), summary-based MR (SMR, for mRNA), and colocalization analysis (for coding genes).Phenomewide MR (PheWAS) analysis, bulk RNA sequencing (RNA-seq) analysis, single-cell RNA sequencing analysis (scRNA-seq), candidate drugs prediction, and Schrodinger molecular docking were performed to provide valuable perspective for targeting drugs development and investigating biological mechanisms.Results: Fifteen druggable genes were identified to have causal associations with AKI risk (FDR <0.05, PSMR < 0.05), of which six targets (PDIA6, GRIK4, MBNL1, CARM1, LRPAP1, and TNFRSF14) showed significant changes in their transcriptional levels in human AKI samples compared to healthy controls (P <0.05).Our results further suggested that genetical inhibition of MNBL1 had a significant association with a lower risk of AKI after validation by co-localization analysis.GSVA analysis indicated that MNBL1 overexpression may be involved in adipocytokine signalling pathway, RIG-I-like receptor signalling pathway, apoptosis, and JAK-STAT signalling pathway (P <0.05, for all).In addition, the expression of MBNL1 in AKI showed a positive correlation with resting memory CD4 T cells (r 0.586, P 0.00614), but negative associations with plasma cells, CD8+ T cells and regulatory T cells (P < 0.05, for all).Further PheWAS revealed no potential side effects of treatments targeting MNBL1.Conclusions: Our study provides genetic evidencesupportingthe potential effects of targeting MBNL1 for AKI treatment, which may be useful for prioritizing drug development.I have no potential conflict of interest to disclose.I did not use generative AI and AI-assisted technologies in the writing process.