Novel genetic insights into the roles of amino acids in metabolic dysfunction-associated steatotic liver disease

Abstract Abstract Background The liver metabolizes amino acids, but previous studies show that amino acids have significant effects also on cardiometabolic diseases like Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Our study investigates the genetic aspects of amino acids in MASLD, explores their causal links, accounting for obesity's influence, and investigates their potential in predicting MASLD complications Methods Using UK Biobank, we examined the observational associations of ten amino acids with MASLD in a cohort of 72,626 cases and 128,102 controls. We used Mendelian randomization (MR) to investigate the relationships between amino acids and MASLD, considering the impact of obesity. Survival analysis assessed the link between baseline amino acid levels and the incidence of major outcomes in 15 year follow-up. Results Nine amino acids showed significant association with MASLD. We observed that higher levels of genetically predicted leucine and valine were associated with an increased risk of MASLD. Among them, valine appeared to independently mediate the link between obesity and MASLD, suggesting a unique role in MASLD beyond its association with obesity. Moreover, an increased risk of genetically predicted MASLD was associated with higher phenylalanine levels. Elevated phenylalanine levels in MASLD patients were linked to increased risks of future metabolic dysfunction-associated steatohepatitis (MASH), hepatocellular carcinoma, cirrhosis, heart failure, stroke, and mortality. Conclusion Our results suggest that valine and leucine may cause incident MASLD, presenting as potential therapeutic targets for MASLD. Alterations in phenylalanine could serve as a novel biomarker for MASLD progression and predicting major outcomes in MASLD patients.