Objective:

To identify the association between GCKR rs1260326 and FGF21 rs838133 polymorphisms and MASLD susceptibility compared to healthy controls, and to evaluate their role in disease progression from MASLD to MASH, including their potential as non-invasive biomarkers.

Key Findings:

• GCKR rs1260326 variant enhances glycolytic throughput and triglyceride synthesis, linking it to hypertriglyceridemia and hepatic fat accumulation, which may inform treatment strategies.
• FGF21 levels are elevated in obesity and fatty liver disease, indicating a compensatory response to metabolic stress, suggesting potential therapeutic targets.
• Genetic variation in FGF21, particularly rs838133, is associated with adverse metabolic traits and may influence susceptibility to hepatic steatosis, warranting further investigation.

Interpretation:

The study highlights the integrated role of GCKR and FGF21 genetic variants in MASLD and MASH, suggesting their potential as non-invasive biomarkers for metabolic risk assessment and clinical management.

Limitations:

• The study's cross-sectional design limits causal inferences, making it difficult to establish direct relationships between genetic variants and disease progression.
• The sample size may restrict the generalizability of findings, indicating a need for larger, multi-center studies to validate results.

Conclusion:

This research underscores the importance of genetic markers in understanding MASLD and MASH progression, advocating for further studies to validate these findings in larger populations and explore their clinical applications.