Journal Article

Genetically predicted plasma levels of amino acids and metabolic dysfunction-associated fatty liver disease risk: a Mendelian randomization study

Zeng, Jing, Zhao, Jian, Targher, Giovanni, Li, Fei, Zhu, Cairong, Li, Xuechao, Liu, Dong, Zhang, Jun, Fan, Jian-Gao

2023

Overview

Background Emerging metabolomics-based studies suggested links between amino acid metabolism and metabolic dysfunction-associated fatty liver disease (MAFLD) risk; however, whether there exists an aetiological role of amino acid metabolism in MAFLD development remains unknown. The aim of the present study was to assess the causal relationship between circulating levels of amino acids and MAFLD risk. Methods We conducted a two-sample Mendelian randomization (MR) analysis using summary-level data from genome-wide association studies (GWAS) to evaluate the causal relationship between genetically predicted circulating levels of amino acids and the risk of MAFLD. In the discovery MR analysis, we used data from the largest MAFLD GWAS (8434 cases and 770,180 controls), while in the replication MR analysis, we used data from a GWAS on MAFLD (1483 cases and 17,781 controls) where MAFLD cases were diagnosed using liver biopsy. We used Wald ratios or inverse variance-weighted (IVW) methods in the MR main analysis and weighted median and MR-Egger regression analyses in sensitivity analyses. Furthermore, we performed a conservative MR analysis by restricting genetic instruments to those directly involved in amino acid metabolism pathways. Results We found that genetically predicted higher alanine (OR = 1.43, 95% CI 1.13–1.81) and lower glutamine (OR = 0.83, 95% CI 0.73–0.96) levels were associated with a higher risk of developing MAFLD based on the results from the MR main and conservative analysis. The results from MR sensitivity analyses and complementary analysis using liver proton density fat fraction as a continuous outcome proxying for MAFLD supported the main findings. Conclusions Novel causal metabolites related to MAFLD development were uncovered through MR analysis, suggesting future potential for evaluating these metabolites as targets for MAFLD prevention or treatment.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Alanine / Amino acid metabolism / Amino acids / Amino Acids - genetics / Analysis / Biobanks / Biomedicine / Biopsy / Causality / Data analysis / Electronic health records / Estimates / Fatty liver / Genetic analysis / Genetic susceptibility / Genome-wide association studies / Genome-Wide Association Study / Genomes / Genomics / Glutamine / Health aspects / Health risks / Humans / Liver / Liver diseases / MAFLD / Medical research / Medicine / Medicine & Public Health / Medicine, Experimental / Mendelian randomization / Mendelian Randomization Analysis / Meta-analysis / Metabolism / Metabolites / Metabolomics / Non-alcoholic Fatty Liver Disease - epidemiology / Non-alcoholic Fatty Liver Disease - genetics / Pathogenesis / Physiological aspects / Plasma levels / Prevention / Proton density (concentration) / Randomization / Regression analysis / Research Article / Risk / Risk factors / Sensitivity analysis / Standard scores / Transplantation / Type 2 diabetes