Biol Trace Elem Res. 2023 Jan 12. doi: 10.1007/s12011-023-03554-x. Online ahead of print.
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 (I2 = 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.