The causal effect of mTORC1-dependent circulating protein levels on nonalcoholic fatty liver disease: A Mendelian randomization study

Abstract

Background: The mechanistic target of rapamycin (mTOR) signal pathway plays a crucial role in the development of nonalcoholic fatty liver disease (NAFLD). However, the causal effect of mTOR downstream proteins on NAFLD remains unknown.

Aims: We conducted a two-sample Mendelian randomization (MR) study to investigate whether the mTOR-dependent circulating proteins, including Eukaryotic Initiation Factor 4E Binding Proteins (eIF4EBPs), Ribosomal Protein S6K kinase 1 (RP-S6K), Eukaryotic Initiation Factor 4E (eIF4E), Eukaryotic Initiation Factor 4A (eIF4A) and Eukaryotic Initiation Factor 4 G (eIF4G), have causal effects on the risk of NAFLD.

Methods: The causal estimate was evaluated with the inverse-variance weighted (IVW) method in discovery stage and validation stage. The single-nucleotide polymorphisms (SNPs) were selected to genetically predict exposures from Genome-Wide Association Studies (GWAS). Exposures with statistically significant effects in the discovery dataset would be further validated in the validation dataset.

Results: MR study revealed that eIF4E had a causal effect on NAFLD in both discovery stage (OR = 1.339, P = 0.037) and validation stage (OR = 1.0007, P = 0.022). Sensitivity analyses confirmed robustness of the results.

Conclusion: The genetically predicted higher level of mTOR-dependent eIF4E in plasma might have a causal effect on the occurrence of NAFLD.

Keywords: Causal association; Mendelian randomization; Nonalcoholic fatty liver disease; mTORC1.