Monocyte Immunometabolic Axis Linking Type 2 Diabetes to Coronary Artery Disease Revealed by Multi-Omics Integration and Mendelian Randomization

BACKGROUND: Type 2 diabetes (T2D) substantially increases coronary artery disease (CAD) risk, with residual risk unexplained by conventional factors. Immunometabolic dysregulation, particularly in monocytes, is implicated, but causal cell type-resolved evidence is limited. METHODS AND RESULTS: We integrated peripheral blood mononuclear cells' bulk and single-cell transcriptomes, identifying 1,799 differentially expressed genes enriched in immune and metabolic pathways. Two-sample Mendelian randomization identified 10 genes showing genetically predicted associations with both T2D and CAD. Among these, ADM, PGD, and ATG7 showed consistent genetically predicted associations with higher CAD risk. Single-cell analyses localized these genes to monocyte subsets and revealed enhanced intercellular communication with vascular cells. The genes also showed good discriminatory performance for CAD in T2D (AUCs 0.741-0.837). CONCLUSIONS: Multi-omics integration and genetic analyses supported a monocyte-centered immunometabolic framework involving ADM, PGD, and ATG7 that was consistent with elevated CAD risk in T2D, and generated testable hypotheses.