Mendelian Randomization Study Suggests Circulating Copper Level as a Risk Factor for Liver Cirrhosis

Cirrhosis is a serious liver disease with an unclear etiology and pathogenesis. Previous studies suggest a correlation between circulating copper and cirrhosis. However, whether circulating copper is a risk factor for cirrhosis is currently controversial because the liver is a major organ of copper metabolism and cirrhosis affects copper circulation. To address this, we used a mendelian randomization to explore the effect of circulating copper concentration on the risk of cirrhosis. We selected instrumental variables (IVs) of circulating copper from genome-wide association studies and analyzed two datasets from FinnGen, one for cirrhosis in general and the other for cirrhosis caused by non-alcoholic fatty liver disease (NAFLD). The inverse-variance weighted method was primarily used for mendelian randomization analysis. We created two SNP IVs that were associated with circulating copper, and their genetic associations with cirrhosis were extracted from the two datasets. The cirrhosis-related dataset included 811 cirrhosis patients and 273,592 controls, while the dataset for cirrhosis caused by NAFLD included 437 cirrhosis patients and 216,861 controls. Mendelian randomization analysis predicted a significant association between higher levels of circulating copper and increased risk of cirrhosis of liver (OR = 1.82, 95% CI: 1.30 to 2.54, P  < 0.001). Additionally, higher levels of circulating copper were also associated with increased risk of cirrhosis of liver caused by NAFLD (OR = 1.68, 95% CI: 1.08 to 2.60, P  = 0.021). The study suggests that higher levels of circulating copper may be a pathogenic risk factor for cirrhosis, providing important insights for the prevention and treatment of cirrhosis.