Department of Gastroenterology, Liyuan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430077, China.
Lipids Health Dis. 2023 Jul 31;22(1):110. doi: 10.1186/s12944-023-01877-1.
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.
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.
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).
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.
先前的研究表明，低密度脂蛋白胆固醇（LDL-C）与肝细胞癌（HCC）有关；然而，由于研究结果相互矛盾以及混杂因素的干扰，两者之间的因果关系尚未得到证实。本研究采用孟德尔随机化（MR）方法来探究 LDL-C 与 HCC 之间的因果关系，并确定中介因素。
从公共数据库中获取 LDL-C、HCC 和冠心病（CAD）全基因组关联研究（GWAS）数据。为了探究因果关系，主要分析方法为逆方差加权（IVW）。MR-Egger、简单模式、加权中位数（WM）和加权模式被用作补充分析方法。此外，还检测了水平异质性。为了评估 MR 结果的稳定性，采用了“逐一剔除”方法。多变量 MR（MVMR）用于校正可能影响因果关系的混杂因素，同时进行中介分析以探究潜在的中介效应。最后，我们使用 HCC 风险来推断 LDL-C 水平的反向因果关系。
随机效应 IVW 结果显示（LDL-C-HCC：比值比（OR）= 0.703，95%置信区间（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），表明 LDL-C 水平与 HCC 风险降低之间存在因果关系。通过 MVMR，在相互校正后，LDL-C 和 CAD 对 HCC 的因果效应仍然显著（P<0.05）。通过中介分析，证明 CAD 介导了 LDL-C 和 HCC 之间的因果关系，并且对 HCC 的中介效应比例为 58.52%。反向 MR 表明 HCC 可以通过负相关影响 LDL-C 水平（OR=0.979，95%CI=[0.961, 0.997]，P=0.025）。
本 MR 研究证实了 LDL-C 水平与 HCC 风险之间的因果关系，CAD 起中介作用。这可能为 HCC 发生和发展机制提供新的视角，以及为治疗提供新的代谢干预靶点。
