Abstract
OBJECTIVE: The relationship between metabolic syndrome (MetS) and venous thromboembolism (VTE) remains controversial. To clarify this, we conducted a two-step Mendelian randomization (MR) study to elucidate these independent causal associations and to investigate the potential mediating effects of circulating adipokines and coagulation factors. METHODS: Two-sample MR was employed to explore the causal associations between MetS components and VTE and its subtypes, including pulmonary embolism (PE) and deep vein thrombosis (DVT). Multivariable MR (MVMR) assessed independent effects, while mediation analyses evaluated the mediating roles of adipokines and coagulation factors. The random-effects inverse-variance weighting was adopted as the primary method, and MR-Egger and weighted median methods were used as supplementary analyses. Cochran's Q test was used to assess heterogeneity, and both the MR-Egger intercept test and Bayesian colocalization analysis were performed to detect horizontal pleiotropy. RESULTS: In the two-sample MR analysis, we found that genetically predicted elevated systolic blood pressure (SBP) is associated with a reduced risk of VTE (OR = 0.99, p = 6.28e-06), PE (OR = 0.99, p = 4.97e-04), and DVT (OR = 0.98, p = 1.15e-08), while higher waist circumference (WC) increases the risk of VTE (OR = 1.65, p = 4.11e-10), PE (OR = 1.74, p = 1.99e-07), and DVT (OR = 1.76, p = 2.20e-08). MVMR analysis showed that both SBP and WC were independently associated with VTE, PE, and DVT. Further mediation analysis revealed that coagulation factor VIII (FVIII) mediated 18.97% of the effect of SBP on VTE, 12.95% on PE, and 14.14% on DVT. Leptin was found to mediate 50.69% of the effect of WC on VTE, 58.12% on PE, and 51.93% on DVT. These findings were replicated in independent samples. Sensitivity analyses excluded the possibility of horizontal pleiotropy and reverse causation. CONCLUSION: Our MR analysis suggests that SBP among the components of MetS is negatively causally associated with VTE and its subtypes, while WC shows a positive causal association. Furthermore, FVIII and leptin play a key mediating role in these relationships. These findings illuminate the mechanisms linking metabolic factors to thrombotic risks, offering novel insights for targeted interventions.