Mapping the Four Adiposity Axes–Inflammatory Cytokine–Venous Thromboembolism Risk Landscape: A Two-Step Mediation Mendelian Randomization Analysis

Background Obesity is heterogeneous; standard metrics (BMI, waist–hip) conflate fat distribution with muscle, limiting causal inference for venous thromboembolism (VTE). This Mendelian randomization (MR) study leverages four magnetic resonance imaging (MRI)-defined adiposity axes to assess VTE causality and inflammatory cytokines mediation. Methods Independent genome-wide significant instruments were selected from dates of the general-obesity, lower-body fat, muscle-dominant, and peripheral fat axes. Outcomes were VTE and its subtypes—deep vein thrombosis (DVT) and pulmonary embolism (PE)—from FinnGen-R12, ensuring non-overlapping samples. The primary analysis used inverse-variance weighting with false discovery rate (FDR) control. Robustness was evaluated using eight complementary MR estimators alongside tests for horizontal pleiotropy and heterogeneity. Two-step mediation MR was used to investigate the obesity-inflammation-thrombosis pathway. Results Genetically proxied general-obesity axis increased risks of VTE (OR 1.431, 95% CI 1.152-1.778), DVT (OR 1.646, 95% CI 1.124-2.410), and PE (OR 1.273, 95% CI 1.150-1.410); The lower-body-fat axis also raised VTE (1.246, 1.141-1.361, 1.20 × 10 −5 ) and DVT (1.216, 1.039-1.424, 0.036); all P FDR < 0.05. Mediation showed CTACK/CCL27 accounted for 8.30% (0.07-16.54%) of General-obesity→ PE, while beta-nerve growth factor (Beta-NGF) and monocyte chemoattractant protein-3 (MCP-3) explained 6.77% (1.25-12.30%) and 6.44% (0.08-12.80%) of general-obesity→VTE. In lower-body-fat→ VTE, platelet-derived growth factor BB (PDGF-BB) and monokine induced by gamma interferon (MIG) mildly masked 5.79–7.89% without altering the direct effect. Conclusions This study indicates that inflammation partly mediates general-obesity axis effects on VTE and its subtypes, while lower-body fat axis confers VTE/DVT risk chiefly via local venous hemodynamic pathways.