Low-density lipoprotein cholesterol and risk of hepatocellular carcinoma: a Mendelian randomization and mediation analysis.

Background: A previous study demonstrated that low-density lipoprotein cholesterol (LDL-C) is associated with hepatocellular carcinoma (HCC); however, the causality between them has not been proven due to conflicting research results and the interference of confounders. This study utilized Mendelian randomization (MR) to investigate the causal relationship between LDL-C and HCC and identify the mediating factors.

Methods: LDL-C, HCC, and coronary artery disease (CAD) genome-wide association study (GWAS) data were obtained from a public database. To investigate causality, inverse variance weighting (IVW) was the main analysis approach. MR‒Egger, simple mode, weighted median (WM), and weighted mode were employed as supplementary analytic methods. In addition, horizontal pleiotropy and heterogeneity were tested. To evaluate the stability of the MR results, a "leave-one-out" approach was used. Multivariate MR (MVMR) was utilized to correct the confounders that might affect causality, and mediation analysis was used to investigate the potential mediating effects. Finally, we used HCC risk to infer the reverse causality with LDL-C level.

Results: Random effects IVW results were (LDL-C-HCC: odds ratio (OR) = 0.703, 95% confidence interval (CI) = [0.508, 0.973], P = 0.034; CAD-HCC: OR = 0.722, 95% CI = [0.645, 0.808], P = 1.50 × 10; LDL-C-CAD: OR = 2.103, 95% CI = [1.862, 2.376], P = 5.65 × 10), demonstrating a causal link between LDL-C levels and a lower risk of HCC. Through MVMR, after mutual correction, the causal effect of LDL-C and CAD on HCC remained significant (P < 0.05). Through mediation analysis, it was proven that CAD mediated the causative connection between LDL-C and HCC, and the proportion of mediating effect on HCC was 58.52%. Reverse MR showed that HCC could affect LDL-C levels with a negative correlation (OR = 0.979, 95% CI = [0.961, 0.997], P = 0.025).

Conclusion: This MR study confirmed the causal effect between LDL-C levels and HCC risk, with CAD playing a mediating role. It may provide a new view on HCC occurrence and development mechanisms, as well as new metabolic intervention targets for treatment.