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

Area of Science:

• Genetics
• Epidemiology
• Cardiovascular Disease

Background:

• Standard obesity metrics like BMI do not differentiate fat distribution, limiting causal inference for venous thromboembolism (VTE).
• Obesity is a heterogeneous condition with varying fat distribution patterns influencing health outcomes.
• Understanding the specific adiposity depots contributing to VTE risk is crucial for targeted prevention.

Purpose of the Study:

• To investigate the causal relationship between different obesity axes and VTE risk using Mendelian randomization (MR).
• To explore the mediating role of inflammatory cytokines in the association between obesity and VTE.
• To differentiate the VTE risk conferred by general obesity versus lower-body fat distribution.

Main Methods:

• Utilized genome-wide significant instruments for four MRI-defined adiposity axes: general obesity, lower-body fat, muscle-dominant, and peripheral fat.
• Assessed VTE and its subtypes (deep vein thrombosis [DVT] and pulmonary embolism [PE]) using data from FinnGen-R12.
• Employed inverse-variance weighting, complementary MR estimators, and two-step mediation MR to analyze causality and mediation pathways.

Main Results:

• The general obesity axis significantly increased risks for VTE, DVT, and PE (all P_FDR < 0.05).
• The lower-body fat axis also elevated risks for VTE and DVT (P_FDR < 0.05).
• Inflammatory mediators like CTACK/CCL27, Beta-NGF, and MCP-3 partially explained the association between general obesity and VTE/PE.

Conclusions:

• Inflammation partially mediates the link between general obesity and VTE, including its subtypes.
• Lower-body fat accumulation primarily contributes to VTE/DVT risk through local venous hemodynamic pathways.
• This study highlights the importance of considering fat distribution in VTE risk assessment and prevention strategies.