Plasma phospholipid arachidonic acid in relation to non-alcoholic fatty liver disease: Mendelian randomization study

•The causality of associations of plasma phospholipid arachidonic acid with non- alcoholic fatty liver disease, cirrhosis, and liver cancer is uncertain.•Genetically predicted higher levels of plasma phospholipid arachidonic acid were causally associated with an increased risk of non-alcoholic fatty liver disease and cirrhosis.•Genetically predicted higher levels of arachidonic acid were associated with increased levels of alanine aminotransferase. The role of plasma phospholipid arachidonic acid (AA) in the development of non-alcoholic fatty liver disease (NALFD), cirrhosis, and liver cancer remains unclear. This study aimed to determine the causality of the associations of plasma phospholipid AA with NALFD, cirrhosis, and liver cancer using Mendelian randomization analysis. Nine independent single-nucleotide polymorphisms associated with plasma phospholipid AA at the genome-wide significance were used as instrumental variables. Summary-level data for three outcomes were obtained from 1) a genome-wide association study for NAFLD, 2) the UK Biobank study, and 3) the FinnGen study. The sensitivity analysis excluding the pleiotropic variant rs174547 in the FADS1 gene was performed. Estimates from different sources were combined using the fixed-effects meta-analysis method. Per standard deviation increase in AA levels, the combined odds ratio was 1.06 (95% confidence interval, 1.02–1.11; P = 0.008) for NAFLD, 1.05 (95% confidence interval, 1.01–1.09; P = 0.009) for cirrhosis, and 0.99 (95% confidence interval, 0.94–1.05; P = 0.765) for liver cancer. The associations remained stable in the sensitivity analysis excluding rs174547. This study suggests potential causal associations of high levels of plasma phospholipid AA with the risk of NAFLD and cirrhosis.