Circulating inflammatory proteins may be potential drug targets for Idiopathic Membranous Nephropathy: proteome-wide Mendelian Randomization and colocalization analysis

• DOI: 10.1101/2023.12.11.23299722
• Publication Date: 2023-12-14T04:45:16Z
• Authors: Zhihang Su; Qingqing Rao; Di Wu; Zheng Yin; Wen Liu; Qijun Wan
• Keywords: Mendelian Randomization; Genome-wide Association Study; Proteome

Abstract Background Idiopathic membranous nephropathy (IMN) is a predominant cause of nephrotic syndrome among adults. Existing drugs are ineffective in about one-third IMN patients, and the high recurrence rate makes them far from satisfactory. Therefore, it imperative to find new therapeutic targets for nephropathy. Circulating inflammatory proteins plasma have been found be related disease prognosis yet causal relationship between still remains unclear. A better understanding response can help us understand occurrence IMN, as well good way targets. In this study, we aim use proteome-wide Mendelian Randomization colocalization analysis identify potential IMN. Methods We selected genetic instrumental variables (IVs) 91 protein quantitative trait locus (pQTL) data obtained 14824 European population samples by Zhao JH et al. 2023 exposure factors. The outcome variable was Genome-Wide Association Study (GWAS) on which involved 2150 cases 5829 controls across five cohorts. To investigate associations risk, conducted two-sample bi-directional MR analysis, sensitivity Bayesian colocalization, phenotype scanning, Protein-Protein Interaction (PPI) network. Results uncovered 2 factors associated with TNF-beta [(Tumor Necrosis Factor-beta) (IVW, OR=1.483, 95%CI=1.186-1.853, P=0.0005, P FDR =0.046)] an increased risk IL-5 [(Interleukin-5) OR=0.482, 95%CI=0.302-0.770, P=0.002, =0.097)] protective effects against After False Discovery Rate multiple correction they remain significant. None these exhibited reverse relationship. provided evidence that share variants [posterior probability hypothesis 4 (PPH4) = 0.88]. Utilizing PPI network, identified several previously mentioned proteins. Notably, were linked Nuclear Factor Kappa B Subunit 1 (NFKB1). Conclusions Our exhaustive suggests causative impact levels genetically predisposed These hold promising treatment, thus necessitating further clinical investigation.