Causal relationships of total testosterone and bioavailable testosterone with aortic aneurysm: A Mendelian randomization study

Abstract Objective To explore the causal relationships between plasma total testosterone (TT), bioavailable testosterone (Bio-T) levels and the pathogenesis of aortic aneurysm (AA) using Mendelian randomization (MR). Methods Single nucleotide polymorphisms (SNPs) strongly associated with TT and Bio-T (P<5×10-10) and with low bias were selected from the IEU Open GWAS public genome database as instrumental variables, with AA as the outcome. The inverse variance weighted (IVW) method served as the primary analytical approach, complemented by MR-Egger regression, weighted median estimation (WME), simple mode, and weighted mode analyses. Sensitivity analyses were conducted using Cochran’s Q test, MR-Egger intercept test, MR-PRESSO test, leave-one-out analysis, and funnel plot inspection, with statistical significance set at P<0.05. Results Two-sample MR analyses revealed causal associations between both TT and Bio-T levels and AA risk, with consistent directional results from MR-Egger regression and WME. MR analysis indicated heterogeneity for the causal association between TT and AA (Cochran’s Q=132.081, P=0.024); MR-PRESSO identified no outlier SNPs, prompting adoption of the random-effects model as the primary result (IVW: OR=0.856, 95%CI: 0.744 to 0.985, P=0.030). The causal effect of Bio-T (IVW: OR=0.551, 95%CI: 0.304 to 0.998, P=0.049) on AA incidence was stronger than that of TT (OR=0.856). Progressive stringent SNP selection thresholds (down to P<5×10-33) and a suite of sensitivity analyses confirmed the robustness of the causal association between Bio-T and AA. Conclusion Both plasma TT and Bio-T levels are causally associated with AA occurrence, with Bio-T conferring a stronger and more robust causal effect. Maintaining healthy, adequate plasma testosterone levels, particularly Bio-T levels, markedly reduce AA risk, offering novel targets and insights for AA prevention and treatment strategies.