Mendelian randomization analysis of free cholesterol in VLDL subfractions and the risk of colorectal cancer

This study analysed the causal relationships between free cholesterol-to-total lipid ratios in different very low-density lipoprotein (VLDL) subfractions and the risk of colorectal cancer (CRC) via a two-sample Mendelian randomization (MR) approach. Genetic variants associated with free cholesterol-to-total lipid ratios in chylomicrons, as well as extremely large, very large, large, medium, small, and very small VLDL subfractions, were identified from genome-wide association studies and selected as instrumental variables. Five analytical methods, including inverse variance weighted (IVW), MR‒Egger, weighted median, weighted mode, and simple mode, were implemented for MR analysis. Elevated free cholesterol-to-total lipid ratios in very large VLDL (odds ratio (OR)=1.25; 95% confidence interval (CI): 1.06–1.49; P =9.6e–3), medium VLDL (OR=1.20; 95%CI: 1.04–1.40; P =0.01), small VLDL (OR=1.17; 95%CI: 1.01–1.35; P =0.04), and very small VLDL (OR=1.29; 95%CI: 1.08–1.54; P =4.8e–3) subfractions were found to be associated with an increased risk of CRC. No significant associations were detected between the risk of CRC and the free cholesterol-to-total lipid ratios in chylomicrons or the extremely large VLDL subfraction. Conclusions : MR analysis provided evidence for a causal association between elevated free cholesterol-to-total lipid ratios in very large, medium, small, and very small VLDL subfractions and an increased risk of CRC. These findings suggest the potential mechanistic role of altered VLDL metabolism in colorectal carcinogenesis and may inform novel therapeutic and preventive strategies.