Abstract
BACKGROUND: Previous studies have investigated the association between immune inflammation, metabolism and erectile dysfunction (ED). However, these studies are limited by biases, confounding factors, and reverse causality, failing to establish causality. We conducted a two-sample Mendelian randomization (MR) study to elucidate the causal relationships between immune cells, inflammatory cytokines, plasma metabolites, and the risk of ED. METHODS: Data on 91 inflammatory cytokines (n=14,736), 731 immune phenotypes (n=3,757) and 1,400 circulating metabolites (n=8,000) were obtained from genome-wide association studies (GWAS) as exposures, while ED data were sourced from the Integrative Epidemiology Unit (IEU) Open GWAS database (n=223,805) as outcomes. A two-sample MR analysis was performed to determine the relationships between exposures and outcomes. The inverse variance weighted (IVW) method was used as the primary MR analysis approach, supplemented by additional methods. Sensitivity analyses, including Cochran's Q test for heterogeneity and MR-Egger intercept for horizontal pleiotropy, were conducted to assess the robustness of the MR results. RESULTS: At a significance level of P<0.01, we identified 12 factors associated with ED: five immune cells, one inflammatory cytokine, two metabolites, and four metabolite ratios. Specifically, CD19 on immunoglobulin D- (IgD-) CD38+ B cells [odds ratio (OR) =1.17; 95% confidence interval (CI): 1.06-1.30], CD4 on terminally differentiated CD4+ T cells (OR =1.07; 95% CI: 1.02-1.12), CD25 on IgD+ CD38dim B cells (OR =1.05; 95% CI: 1.01-1.09), CD25 on IgD+ CD24- B cells (OR =1.04; 95% CI: 1.01-1.07), and IgD on IgD+ B cells (OR =0.88; 95% CI: 0.79-0.97) were associated with ED. Among inflammatory cytokines, only elevated levels of urokinase-type plasminogen activator (uPA) significantly reduced the risk of ED (OR =0.83; 95% CI: 0.73-0.95). Six metabolites, including glycerol levels (OR =1.30; 95% CI: 1.08-1.56), aspartate to N-acetylglucosamine to N-acetylgalactosamine ratio (OR =1.21; 95% CI: 1.07-1.37), cholesterol to taurocholate ratio (OR =1.23; 95% CI: 1.07-1.42), 4-methyl-2-oxopentanoate to 3-methyl-2-oxobutyrate ratio (OR =1.26; 95% CI: 1.07-1.48), alpha-ketoglutarate to kynurenine ratio (OR =0.86; 95% CI: 0.76-0.96), and X-16964 levels (OR =1.24; 95% CI: 1.06-1.45) were significantly associated with ED. Sensitivity analyses did not reveal any heterogeneity or pleiotropy. CONCLUSIONS: Our MR analysis indicates that immune inflammation and metabolism have both inducing and protective effects on ED risk. These findings provide new insights for clinicians regarding the treatment and prevention of ED. Additionally, our study offers novel insights into the pathogenesis of ED.