Lipids, lipid-modifying drug targets with venous thromboembolism: a mendelian randomization study

The role of lipid-lowering therapies (e.g., statins) during anticoagulation for Venous Thromboembolism (VTE) remains unclear. This study investigated the causal role of lipid traits in VTE and evaluated lipid-lowering drug targets using a Mendelian Randomization (MR) approach.

Genetic variants associated with lipid traits and lipid-lowering drug targets were extracted from the Global Lipids Genetics Consortium GWAS. Summary statistics for VTE, Deep Vein Thrombosis (DVT), and Pulmonary Embolism (PE) were obtained from UK Biobank. For associated targets, expression quantitative trait loci data were analyzed using summary-data-based MR. Colocalization analysis assessed shared genetic signals, and molecular docking explored plausible ligand-target binding poses.

Higher triglyceride levels were associated with lower VTE (OR = 0.998, 95% CI: 0.996‒1.000, p = 0.035) and DVT risks (OR = 0.998, 95% CI: 0.997‒1.000, p = 0.012). Genetic mimicry of Lipoprotein Lipase (LPL) enhancement was nominally associated with lower VTE odds (OR = 0.997, 95% CI: 0.995‒1.000, p = 0.02) and with lower PE odds after Bonferroni correction (OR = 0.996, 95% CI: 0.994‒0.998, p = 5.29E-06), but not DVT. LPL expression in whole blood showed a significant MR association with PE (OR = 1.001, 95% CI: 1.000‒1.002, p = 0.039) and moderate colocalization (PP.H4 = 0.68). Molecular docking predicted plausible active-site or allosteric binding poses for three LPL agonists (binding energies ≤ -6.8 kcal/mol).

Genetically proxied LPL enhancement was nominally associated with modestly lower composite VTE risk and was associated with lower PE risk after multiple-testing correction, although no association was observed for DVT. These findings support a potential role for LPL-related pathways in VTE biology and warrant independent genetic and functional validation before clinical translation.