VLDL Phospholipid Composition, Remnant Cholesterol, ApoB , and Coronary Artery Disease: A Network Mendelian Randomization Study

Remnant cholesterol and apolipoprotein B ( ApoB ) are established contributors to coronary artery disease ( CAD ), but their relationship with very‐large VLDL phospholipid composition remains uncertain. We evaluated whether genetically proxied VLDL phospholipid composition is linked to CAD through a connected remnant cholesterol– ApoB axis. Summary‐level GWAS data were analyzed using network Mendelian randomization. Primary pairwise analyses used genome‐wide significant instruments ( P < 5 × 10 −8 ) and inverse‐variance weighted random‐effects models, with weighted median, MR ‐Egger, MR ‐ PRESSO , Steiger directionality, leave‐one‐out analyses, multivariable MR ( MVMR ), and locus‐level colocalization as complementary analyses. Higher VLDL phospholipid ratio was associated with higher remnant cholesterol (β = 0.86, 95% CI 0.74–0.99) and higher CAD risk ( OR = 1.80, 95% CI 1.54–2.11). Remnant cholesterol was associated with higher ApoB (β = 1.04, 95% CI 1.01–1.08), and ApoB with higher CAD risk ( OR = 1.40, 95% CI 1.23–1.59). In MVMR models with adequate conditional instrument strength, VLDL phospholipid ratio remained associated with CAD after adjustment for remnant cholesterol ( OR = 1.44, 95% CI 1.07–1.94) or ApoB ( OR = 1.60, 95% CI 1.21–2.11), whereas their conditional effects were not independently significant. Remnant cholesterol and ApoB showed near‐complete genetic collinearity, limiting reliable separation of their independent effects. colocalization supported shared causal signals at multiple loci. The findings support a genetically connected VLDL–remnant cholesterol–ApoB lipid axis associated with CAD, but do not establish formal serial mediation. VLDL phospholipid composition may capture CAD‐relevant biology not fully explained by remnant cholesterol or ApoB alone.