School of Public Health, Zhejiang Chinese Medical University, Binwen Road 548, Hangzhou, 310053, Zhejiang, China.
The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China.
Biol Trace Elem Res. 2023 Oct;201(10):4649-4656. doi: 10.1007/s12011-023-03554-x. Epub 2023 Jan 12.
The association between circulating copper and the risk of liver cancer has been investigated by previous studies, while the findings were inconsistent. Thus, we aimed to evaluate the association between circulating copper and liver cancer by using meta-analysis and Mendelian randomization (MR). For meta-analysis, PubMed and Web of Science were searched to identify eligible studies published before April 4, 2022. Standardized mean difference (SMD) with 95% confidence interval (CI) in circulating copper level between liver cancer patients and controls were pooled. Furthermore, we selected genetic instruments for circulating copper from a genome-wide association study (GWAS) to conduct MR analysis. The summary statistics related to liver cancer were obtained from two large independent cohorts, UKBB and FinnGen, respectively. MR analysis was performed mainly by inverse-variance weighted (IVW) approach, followed by maximum-likelihood method as sensitivity analysis. In meta-analysis of eight studies, circulating copper was found to be higher in liver cancer patients (SMD: 1.65; 95% CI: 0.65 to 2.65) with high heterogeneity (I = 96.40%, P = 0.001). However, inconsistent findings were observed among subgroups with high evidence. In MR analysis, genetically predicted circulating copper was not significantly associated with the risk of liver cancer by IVW in UKBB (OR: 1.38; 95% CI: 0.72 to 2.65) and FinnGen (OR: 1.10; 95% CI: 0.69 to 1.73) separately, and the pooled results produced similar results (OR: 1.18, 95% CI: 0.81 to 1.72). Moreover, non-significant finding was confirmed by using maximum-likelihood method. There is no sufficient evidence to demonstrate that high levels of circulating copper increase the risks of liver cancer.
先前的研究已经探讨了循环铜与肝癌风险之间的关联，但研究结果并不一致。因此，我们旨在通过荟萃分析和孟德尔随机化（MR）来评估循环铜与肝癌之间的关联。对于荟萃分析，我们检索了 PubMed 和 Web of Science，以确定截至 2022 年 4 月 4 日之前发表的符合条件的研究。汇总了肝癌患者和对照组之间循环铜水平的标准化均数差值（SMD）及其 95%置信区间（CI）。此外，我们从全基因组关联研究（GWAS）中选择了用于循环铜的遗传工具来进行 MR 分析。与肝癌相关的汇总统计数据分别从两个大型独立队列 UKBB 和 FinnGen 中获得。MR 分析主要通过逆方差加权（IVW）方法进行，随后进行最大似然法作为敏感性分析。在八项研究的荟萃分析中，发现肝癌患者的循环铜水平更高（SMD：1.65；95%CI：0.65 至 2.65），且存在高度异质性（I=96.40%，P=0.001）。然而，在具有高证据的亚组中观察到不一致的结果。在 MR 分析中，通过 IVW 在 UKBB（OR：1.38；95%CI：0.72 至 2.65）和 FinnGen（OR：1.10；95%CI：0.69 至 1.73）中，遗传预测的循环铜与肝癌风险之间没有显著关联，并且汇总结果产生了类似的结果（OR：1.18，95%CI：0.81 至 1.72）。此外，最大似然法也证实了非显著结果。没有足够的证据表明高水平的循环铜会增加肝癌的风险。
