Abstract
BACKGROUND: Some studies suggest a potential association between plasma lipidome and erectile dysfunction (ED), but the underlying mechanism and whether circulating inflammatory proteins act as mediators remain unclear. The purpose of this study was to investigate the potential causal relationships between plasma lipidome, inflammatory proteins, and ED. METHODS: Plasma lipidome, circulating inflammatory proteins, and ED cases were identified based on the summary data from several large-scale genome-wide association studies (GWAS). The causal relationships of plasma lipidome and circulating inflammatory proteins with ED were explored by a bidirectional two-sample, two-sample Mendelian randomization (MR) method. The inverse variance weighted (IVW) method was used as the primary analytical method. MR-Egger and the weighted median (IVW) methods were utilized as supplementary analytical techniques. Sensitivity analyses including MR-Pleiotropy RESidual Sum and Outlier method (PRESSO), Cochran's Q test, and MR-Egger intercept test were conducted to address heterogeneity and horizontal pleiotropy. RESULTS: Ceramide (d42:2) and triacylglycerol (56:3) were found to be associated with an increased risk of ED, while phosphatidylethanolamine (O-18:1_18:2) and phosphatidylinositol (18:1_18:1) were linked to a decreased risk of ED. Interleukin-1α (IL-1α), IL-7, IL-17C, and the tumor necrosis factor (TNF) receptor superfamily member 9 (TNFRSF9) positively affected ED. Conversely, leukemia inhibitory factor and urokinase-type plasminogen activator (uPA) showed a negative impact. Mediation analysis indicated that the uPA mediated between Triacylglycerol (56:3) and ED, accounting for a mediation proportion of -14.71%. CONCLUSIONS: There was a causal relationship between plasma lipidome and circulating inflammatory proteins with ED. Circulating inflammatory proteins appeared to mediate between triacylglycerol (56:3) levels and ED.