Abstract
BACKGROUND: This study aims to explore the causal relationship between the expression of succinylation-related genes and erectile dysfunction (ED). METHOD: Through a literature review, we identified 19 succinylation-related genes and intersected them with cis-expression Quantitative Trait Loci (cis-eQTL) data from the eQTLGen Consortium, ultimately selecting 16 genes with available cis-eQTL data. Subsequently, we downloaded genomic data related to erectile dysfunction (ED) from 223,805 European male participants in the IEU OpenGWAS project and performed a two-sample Mendelian Randomization (MR) analysis. Summary-based Mendelian Randomization (SMR) analysis and ELISA testing further confirmed the statistical association between ENO1 gene expression and ED risk. Mediation analysis was used to explore the potential regulatory role of DNA methylation in the relationship between gene expression and ED. RESULT: Through MR analysis, a significant causal relationship between the ENO1 gene and ED was identified. The results indicated that the expression of the ENO1 gene has a significant causal effect on the risk of ED (OR: 1.2388, 95% CI: 1.0708-1.4332, p < 0.05). SMR analysis further confirmed the causal relationship between ENO1 gene expression and ED (SMR_p-value = 0.0040). Mediation analysis suggested that the methylation site cg06972019 may inhibit the occurrence of ED by regulating ENO1, with the mediation proportion accounting for 67.6% of the total effect (P = 0.0013). ELISA results showed that the serum ENO1 levels in ED patients were significantly higher than those in the healthy control group (p < 0.05), validating the potential role of ENO1 in ED. CONCLUSION: This study revealed the potential causal relationship of the ENO1 gene in the development of ED through Mendelian Randomization and SMR analysis, further validating the association between gene expression and ED. The overexpression of the ENO1 gene may be regulated by the methylation site cg06972019. These findings provide new insights into the molecular mechanisms of ED and may offer new biomarkers for the early diagnosis and targeted treatment of ED.