The ratio of triglycerides to total lipids in chylomicrons and extremely large VLDL, very large VLDL, large VLDL, medium VLDL, and small VLDL has a significant negative causal relationship with Coronary revascularization (ANGIO or CABG). A Mendelian randomization study

BACKGROUND Different lipids and lipoproteins have different relationships with atherosclerotic disease. We did Mendelian randomization study to explore the relationships between them. METHODS We conducted this Mendelian randomization (MR) study to analyze the causal relationship between TG levels/TG to total lipids ratio in lipoprotein subfractions and Coronary revascularization. RESULTS The ratio of TG to total lipids in chylomicrons(CM) and extremely large VLDL(P=2.43e-03, OR: 0.53, 95% CI: 0.36-0.80), very large VLDL(P=7.94e-04, OR: 0.68, 95%CI: 0.55-0.85), large VLDL(P=4.01e-06,OR:0.53,95%CI:0.41-0.69), medium VLDL(P=9.68e-03,OR:0.77,95%CI:0.63-0.94), small VLDL(P=0.02,OR:0.71,95%CI:0.53-0.94) showed a negative causal relationship with coronary revascularization, whereas this ratio of TG to total lipids in very small VLDL, IDL, large LDL, medium LDL, small LDL showed no causal correlation with it. After replacing the TG to total lipids ratio with TG levels the causal relationship became positive (except large VLDL). In contrast, when substituting the TG levels with TG-to-total-lipids ratio in very large HDL, large HDL, and medium HDL particles, their previously no causal relationship with coronary revascularization became positive. Replacing TG levels with the TG-to-total-lipids ratio in in different sizes of VLDL particles enhances the particles’ anti-atherosclerotic effects while reducing pro-atherogenic activity. In contrast, the same replacement in HDL promotes pro-atherogenic effects and diminishes anti-atherogenic properties. This divergence is primarily attributed to their opposing impacts on Cholesteryl Ester Transfer Protein (CETP) function, which critically determines the net atherogenic outcome. CONCLUSIONS This ratio variation across lipoprotein types and sizes differentially modulates CETP activity. When CETP transfers cholesterol esters (CE) from HDL to other lipoproteins — such as chylomicrons (CM), VLDL, IDL, and LDL — these particles become substrates for a broader range of metabolism-related receptors. Outcome 1: If this process enhances receptor binding, it reduces pro-atherogenic effects and may exert anti-atherosclerotic properties. Outcome 2: Conversely, if impaired receptor binding occurs, the accumulation of unprocessed lipoproteins will inevitably promote atherosclerosis. Different lipoproteins can bind to various receptors in tissues and cells, leading to either anti-atherosclerotic or pro-atherogenic effects. The final outcome depends on their net effect, which determines whether different lipoprotein subfractions exhibit a negative, positive, or neutral causal relationship with coronary revascularization.