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

Genetically proxied general-obesity axis increased risks of VTE, DVT, and PE.

• VTE risk: OR 1.431 (95% CI 1.152-1.778), PFDR < 0.05
• DVT risk: OR 1.646 (95% CI 1.124-2.410), PFDR < 0.05
• PE risk: OR 1.273 (95% CI 1.150-1.410), PFDR < 0.05
• Primary analysis used inverse-variance weighting with false discovery rate (FDR) control
• Robustness evaluated using eight complementary MR estimators alongside tests for horizontal pleiotropy and heterogeneity

The lower-body fat axis raised risk of VTE and DVT.

• VTE risk: OR 1.246 (95% CI 1.141-1.361), P = 1.20 × 10-5, PFDR < 0.05
• DVT risk: OR 1.216 (95% CI 1.039-1.424), P = 0.036, PFDR < 0.05
• The lower-body fat axis effect on VTE/DVT was attributed chiefly to local venous hemodynamic pathways rather than inflammation

CTACK/CCL27 mediated a portion of the general-obesity axis effect on PE.

• CTACK/CCL27 accounted for 8.30% (95% CI 0.07-16.54%) of the general-obesity → PE pathway
• This was identified using two-step mediation Mendelian randomization
• The mediation proportion indicates partial inflammatory mediation of obesity-related PE risk

Beta-nerve growth factor (Beta-NGF) and monocyte chemoattractant protein-3 (MCP-3) mediated portions of the general-obesity axis effect on VTE.

• Beta-NGF explained 6.77% (95% CI 1.25-12.30%) of the general-obesity → VTE pathway
• MCP-3 explained 6.44% (95% CI 0.08-12.80%) of the general-obesity → VTE pathway
• Both mediators are inflammatory cytokines identified via two-step mediation MR

In the lower-body fat to VTE pathway, PDGF-BB and MIG acted as mild masking mediators without altering the direct effect.

• Platelet-derived growth factor BB (PDGF-BB) and monokine induced by gamma interferon (MIG) masked 5.79-7.89% of the lower-body-fat → VTE association
• Despite masking, these cytokines did not alter the direct effect of the lower-body fat axis on VTE
• This suggests the lower-body fat axis operates primarily through non-inflammatory (hemodynamic) mechanisms

The study used four MRI-defined adiposity axes to distinguish different fat distribution patterns in relation to VTE.

• The four axes were: general-obesity, lower-body fat, muscle-dominant, and peripheral fat axes
• Instruments were independent genome-wide significant variants selected from GWAS data for each axis
• Outcomes (VTE, DVT, PE) were obtained from FinnGen-R12 with non-overlapping samples ensured
• The approach was designed to overcome limitations of standard metrics (BMI, waist-hip ratio) which conflate fat distribution with muscle