Genotype-First Approach Identifies an Association between rs28374544/FOG2^S657G and Liver Disease through Alterations...

Area of Science:

• Genetics
• Molecular Biology
• Hepatology

Background:

• Metabolic dysfunction-associated Fatty Liver Disease (MAFLD) is a growing cardiometabolic concern.
• Friend of GATA2 (FOG2) regulates hepatic lipid metabolism.
• A specific FOG2 coding variant (rs28374544, FOG2^S657G) is prevalent in individuals of African ancestry and associated with liver injury.

Purpose of the Study:

• To investigate the molecular mechanisms by which the FOG2^S657G variant contributes to MAFLD.
• To identify pathways regulated by the FOG2^S657G variant in liver cells.

Main Methods:

• Meta-analysis of biobank datasets to identify the FOG2 variant.
• Analysis of human induced pluripotent stem cell-derived hepatocytes (iHeps) genomics data.
• Differential Gene Expression and Gene Set Enrichment Analyses.
• In vitro studies using Huh7 hepatoma cells with wild-type FOG2 and FOG2^S657G.

Main Results:

• The FOG2^S657G variant was associated with liver failure/cirrhosis and liver injury.
• mTORC1 signaling was differentially regulated in iHeps with the variant.
• FOG2^S657G expression increased mTORC1 signaling, de novo lipogenesis, and triglyceride synthesis in Huh7 cells.
• FOG2^S657G downregulated oxidative phosphorylation in fatty acid-loaded cells, promoting lipid accumulation.

Conclusions:

• The FOG2^S657G variant may promote MAFLD by activating mTORC1 signaling and increasing lipid synthesis and accumulation.
• This study elucidates a potential molecular pathway linking a specific genetic variant to MAFLD pathogenesis.
• Findings offer insights into the genetic underpinnings of MAFLD and potential therapeutic targets.