GCKR genetic variants and circulating FGF21 define a metabolic risk signature in Metabolic-associated Steatotic Liver disease

Background & Aims: Metabolic dysfunction–associated steatotic liver disease (MASLD) represents a broad clinicopathological spectrum, extending from isolated hepatic steatosis to its progressive inflammatory stage, metabolic dysfunction–associated steatohepatitis (MASH). Interindividual variability in disease onset and progression reflects a complex interplay between metabolic burden and inherited susceptibility. The present study investigated the combined impact of genetic variants in the glucokinase regulatory protein gene (GCKR) and fibroblast growth factor 21 (FGF21), together with circulating FGF21 concentrations, on susceptibility to MASLD and its progression to MASH. Methods: This case-control study enrolled 450 age- and sex-matched participants: 150 patients with MASLD, 150 with fibroscan-confirmed MASH, and 150 healthy controls. Genotyping of GCKR rs1260326 and FGF21 rs838133 polymorphisms was performed using real-time polymerase chain reaction, while serum FGF21 levels were quantified by enzyme-linked immunosorbent assay. Associations with metabolic characteristics, liver function indices, and fibrosis severity were examined using correlation analyses and multivariate logistic regression models. Results : The GCKR rs1260326 TT genotype was significantly overrepresented among patients with MASH (p=0.005) and was associated with higher alanine aminotransferase levels and reduced markers of hepatic synthetic capacity. In parallel, carriers of the FGF21 rs838133 G allele exhibited an increased likelihood of MASLD and a higher propensity for progression to MASH, accompanied by greater insulin resistance and unfavorable lipid profiles. Circulating FGF21 concentrations demonstrated a stepwise increase from controls to MASLD and MASH groups and showed strong diagnostic performance in identifying advanced disease stages. Multivariate analysis confirmed that both serum FGF21 levels and GCKR genetic variation independently predicted the risk of MASH. Conclusions: Genetic variation in GCKR and FGF21, together with altered hepatokine signaling, contributes substantially to metabolic dysregulation and liver disease severity. Integrating genetic profiling with circulating biomarkers may offer a refined strategy for identifying individuals at high risk of MASLD progression and advancing precision-based approaches in metabolic liver disease.