Blood metabolites as mediators in erectile dysfunction: insights from a multi-center proteomics and genetic study

Abstract

Objective: This study aims to identify circulating proteins causally associated with erectile dysfunction (ED) using Mendelian randomization (MR) analysis.

Methods: We utilized two of the largest multi-center proteomics databases as exposures and the FinnGen database as the outcome source. A large-scale two-sample MR analysis, including coloc colocalization analysis and SMR (Summary data-based Mendelian Randomization) analysis, was conducted to evaluate the reliability of proteomic effects on ED outcomes. Additionally, MR mediation analysis involving 1,400 blood metabolites was performed to investigate how these proteins mediate the effect of blood metabolites on ED. Finally, protein-protein interaction analysis, pathway enrichment analysis, druggability assessments, and molecular docking were employed to further elucidate the mechanisms of ED and identify potential therapeutic targets.

Results: Eight circulating proteins (AMN, ESM1, KIR2DL2, PIGR, SPINT1, SPP1, TNFRSF6B, TMEM9) were identified as causally associated with ED based on two-sample MR and coloc colocalization criteria. Among these, five proteins (AMN, ESM1, KIR2DL2, PIGR, TNFRSF6B) satisfied SMR validation, while SPINT1, TMEM9, and SPP1 were excluded. Several of these proteins were found to mediate the relationship between metabolites and ED. These proteins are recognized as either druggable targets or existing drug targets, with molecular docking results demonstrating favorable interactions with various drug candidates.

Conclusion: Using MR analysis, we identified five proteins associated with ED, clarified protein-mediated mechanisms, and proposed promising therapeutic targets for ED.

Keywords: blood metabolites; erectile dysfunction; mendelian randomization; precision therapy; proteomics.

FIGURE 1

Workflow for identifying and validating protein targets associated with erectile dysfunction. This figure illustrates the multi-step process integrating Mendelian randomization, co-localization, and functional analyses to identify potential protein targets for ED.

FIGURE 2

Volcano plot of differentially expressed genes with highlighted protein targets. This volcano plot displays the distribution of differentially expressed genes, with five protein targets (AMN, ESM1, KIR2DL2, PIGR, and TNFRSF6B) specifically annotated as satisfying two-sample Mendelian randomization, colocalization, and SMR analysis criteria.

FIGURE 3

Colocalization analysis of genomic loci and protein targets. This figure presents the colocalization analysis of genomic loci with protein targets, highlighting key regions associated with AMN, ESM1, KIR2DL2, TNFRSF6B, and PIGR. The results demonstrate the overlap of significant loci with identified protein targets, supporting their potential causal role.

FIGURE 4

SMR analysis visualization of protein targets. This figure depicts the SMR (summary data-based Mendelian randomization) analysis results, highlighting the association between genetic loci and protein targets, including AMN, ESM1, KIR2DL2, TNFRSF6B, and PIGR, with significant evidence supporting their causal links.

FIGURE 5

KEGG and GO enrichment analysis of significant protein targets. This figure illustrates the KEGG pathway and Gene Ontology (GO) enrichment analysis for the identified protein targets, highlighting their involvement in key biological processes, molecular functions, and relevant signaling pathways.

FIGURE 6

Protein-protein interaction (PPI) network of identified targets. This figure displays the protein-protein interaction (PPI) network for the five identified targets (AMN, ESM1, KIR2DL2, PIGR, and TNFRSF6B), illustrating their interconnected roles and potential interactions within biological systems. Key nodes represent the protein targets, and edges indicate predicted or known interactions, providing insights into their functional relationships.

FIGURE 7

Structural analysis of protein targets with molecular docking. This figure shows the structural visualization and molecular docking results of the four identified protein targets: (A) AMN, (B) KIR2DL2, (C) PIGR, and (D) TNFRSF6B. The 3D surface representation highlights the binding sites and key residues involved in interactions, providing insights into the structural basis of their functional roles.