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

BackgroundPrevious research has suggested potential links between amino acids and metabolic dysfunction-associated steatotic liver disease (MASLD), but the precise roles of amino acids in MASLD development are not well understood. This study aimed to obtain insights into the relationships between circulating amino acids and MASLD. MethodsUtilizing data from the UK Biobank, we examined the observational associations of ten amino acids with MASLD in a cohort of 72,626 MASLD cases and 128,102 controls. Bi-directional two-sample Mendelian randomization (MR) was conducted using genome-wide association study data to investigate the causal relationships between amino acids and MASLD. Multiple MR methods comprising MR-Egger and MR-PRESSO were applied to assess pleiotropy and heterogeneity, and multivariable MR was conducted to evaluate the impacts of body mass index (BMI) on these associations. Survival analysis assessed the link between baseline amino acid levels and the risk of major outcomes. ResultsWe identified nine amino acids significantly associated with MASLD in the observational study. The genetic predisposition towards higher leucine (odds ratio (OR) [95% confidence interval (CI)]: 2.1 [1.4, 3.2]), valine (OR [95% CI]: 1.8 [1.3, 2.7]), and alanine (OR [95% CI]: 1.4 [1.1, 1.8]) levels were significantly associated with MASLD. By contrast, the genetic predisposition for increased MASLD risk was significantly associated with phenylalanine (beta = 0.05, p = 4.0x10-4). Further analysis showed that valine may mediate the association between BMI and MASLD, and may also have an exclusive effect on MASLD in addition to the effect of obesity (beta = 1.3, p = 1.9x10-4). Elevated phenylalanine levels in MASLD patients were linked with an increased risk of metabolic dysfunction-associated steatohepatitis (MASH), hepatocellular carcinoma, cirrhosis, heart failure, stroke, and mortality. ConclusionWe found genetic associations between circulating branched-chain amino acids, particularly leucine and valine, and MASLD, independent of obesity. Phenylalanine was identified as a potential biomarker for MASLD prognostic complications. These results highlight the importance of amino acid metabolism in MASLD as well as suggest new possibilities for research and therapeutic intervention.