Causal relationship between plasma branched-chain amino acids levels and nonalcoholic fatty liver disease: a bidirectional Mendelian randomization study.

BACKGROUND

Previous studies have revealed a relationship between plasma branched-chain amino acids (BCAAs) levels and non-alcoholic fatty liver disease (NAFLD). However, this connection has not been thoroughly explored due to potential biases such as confounders or reverse causality. We performed a bidirectional Mendelian randomization (MR) analysis to explore the potential causal association between plasma BCAAs levels and NAFLD at the genetic level.

METHODS

Publicly available summarized data from genome-wide association studies (GWASs) on plasma BCAAs levels (n = 115,079) and NAFLD (2275 cases and 375,002 controls) were obtained from Integrative Epidemiology Unit Genome-Wide Association Study Database (IEU GWAS database) and Finnish Genome biobank (FinnGen biobank), respectively. The inverse variance weighted (IVW) method was used in the main analysis, followed by maximum likelihood (ML) method, simple median (SM) method, and Mendelian randomization robust adjusted profile score (MR-RAPS) and leave-one-out method in the sensitivity analyses. Heterogeneity was analyzed using Cochran's Q statistic, and horizontal pleiotropy was assessed via MR-Egger regression.

RESULTS

The bidirectional MR study revealed that genetically determined high plasma valine level was significantly associated with an increased risk of NAFLD via IVW method (odds ratio [OR], 1.944; 95% confidence interval [CI], 1.226-3.084; P = 0.004), with consistent effect estimates across alternative MR methods. Heterogeneity and horizontal pleiotropy were not detected by sensitivity analysis, supporting the reliability of our findings. Results of reverse MR do not support an effect of NAFLD on plasma BCAAs levels at the genetic level.

CONCLUSIONS

The present bidirectional MR study support a potential directional association between genetically predicted higher plasma valine levels and increased susceptibility to NAFLD.