Genetically Predicted β‐Hydroxybutyrate and Coronary Atherosclerosis: Mendelian Randomization and APOE ‐Associated Transcriptomic Signatures in Human Atherosclerotic Plaques

ABSTRACT Aims Ketone bodies are implicated in cardiovascular metabolism, yet the contributions of β‐hydroxybutyrate (BHB), acetoacetate and acetone to coronary atherosclerosis remain unclear. Methods We integrated Mendelian randomization (MR), cross‐trait GWAS analysis, ApoE pQTL‐MR and colocalization to investigate genetic associations with coronary atherosclerosis, complemented by bulk transcriptomic analysis, machine learning‐based signature construction, immune infiltration analysis and single‐cell analysis to characterize APOE ‐associated molecular features in human atherosclerotic plaques. Results Genetically predicted BHB was associated with coronary atherosclerosis risk in univariable MR (OR = 1.59, 95% CI: 1.29–1.95, p = 8.8 × 10 −6 ) and remained significant after mutual adjustment for acetoacetate and acetone (OR = 1.58, 95% CI: 1.14–2.18, p = 0.005), whereas neither acetoacetate nor acetone showed a significant association. Cross‐trait gene prioritization highlighted APOE for further investigation. ApoE pQTL‐MR supported an association between genetically predicted ApoE and coronary atherosclerosis (OR = 1.23, p = 0.003). Weighted gene co‐expression network analysis (WGCNA) and machine‐learning algorithms, including LASSO, random forest, SVM‐RFE and XGBoost, identified an APOE ‐associated five‐gene signature comprising XAF1 , CEP128 , TMEM106A , VEPH1 and ABCB1 . The signature achieved an apparent AUC of 0.956 in GSE43292 and AUCs of 0.974 in GSE100927 and 0.736 in GSE28829. High signature scores were associated with immune‐inflammatory changes. Single‐cell analysis showed enrichment of the signature in macrophages, endothelial cells and fibroblasts, while CellChat analysis identified a macrophage‐centred pattern of inferred cell–cell communication. Conclusions These findings identify BHB as the ketone body most strongly associated with coronary atherosclerosis susceptibility and define an APOE ‐associated multicellular signature in human atherosclerotic plaques with potential value for molecular stratification.