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

Abstract

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.