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

Abstract

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