Lipids, cholesterols, statins and liver cancer: a Mendelian randomization study.

Aim: To investigate the causal relationship of serum lipid indicators and lipid-lowering drugs with the risk of liver cancer using Mendelian randomization study. Methods: A two-sample Mendelian randomization (TSMR) study was performed to investigate the causal relationship between serum levels of lipid indicators and liver cancer, including low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), triglycerides (TG), total cholesterol (TC), Apolipoprotein B (ApoB), and Apolipoprotein A1 (ApoA1).Furthermore, instrumental variable weighted regression (IVW) and summary data-based MR (SMR) analyses were performed to investigate the causal effects of lipid-lowering drugs, including statins and PCSK9 inhibitors, on the risk of liver cancer. Results: Serum LDL-c and serum TC levels showed negatively associated with liver cancer (n = 22 SNPs, OR = 0.363, 95% CI = 0.231 - 0.570; p = 1.070E-5) (n = 83 SNPs; OR = 0.627, 95% CI = 0.413-0.952; p = 0.028). However, serum levels of TG, HDL-c, and ApoA1 did not show any significant correlation with liver cancer. In the drug target MR (DMR) analyses, HMGCR-mediated level of LDL-c showed an inverse relationship with the risk of liver cancer in the IVW-MR analysis (n = 5 SNPs, OR = 0.201, 95% CI = 0.064 - 0.631; p = 5.95E-03) and SMR analysis (n = 20 SNPs, OR = 0.245, 95% CI = 0.065 - 0.926; p = 0.038) However, PCSK9 did not show any significant association with liver cancer based on both the IVW-MR and SMR analyses. Conclusion: Our results demonstrated that reduced levels of LDL-c and TC were associated with an increased risk of liver cancer. Furthermore, lipid-lowering drugs targeting HMGCR such as statins were associated with increased risk of liver cancer.