Alcohol consumption and hepatocellular carcinoma: novel insights from a prospective cohort study and nonlinear Mendelian randomization analysis

Heavy drinking was well associated with an increased risk of hepatocellular carcinoma (HCC), whereas the effect of low-to-moderate drinking on HCC remains under debate. Participants from the UK Biobank with detailed information on alcohol use and free of common diseases were included. Daily pure alcohol intake (g/day) was calculated, and the predominant alcoholic beverage type was assigned for each participant. Additive Cox regression model and nonlinear Mendelian randomization (NLMR) analyses were performed to evaluate the association of alcohol intake with HCC. Of 329,164 participants (52.3% females, mean [SD] age = 56.7 [8.0] years), 201 incident HCC cases were recorded during the median follow-up of 12.6 years. The best-fitted Cox regression model suggested a J-shaped relationship between daily alcohol intake level and HCC risk. However, NLMR analysis did not detect a nonlinear correlation between alcohol use and HCC (nonlinearity P-value: 0.386). The J-shaped correlation pattern was detected only in subjects who mainly drank wine but not in those who mainly drank beer, spirits, or fortified wine. Moderate wine drinking showed a significant alanine transaminase (ALT)- and aspartate aminotransferase-lowering effect compared to that of the nondrinkers. In low-risk populations of HCC including women, people aged