GCKR genetic variants and circulating FGF21 identify a metabolic risk signature in metabolic dysfunction-associated steatotic liver disease

Abstract Background & aims Interindividual variability in metabolic dysfunction–associated steatotic liver disease (MASLD) onset and its progressive inflammatory stage, metabolic dysfunction–associated steatohepatitis (MASH), reflects a complex interplay between metabolic burden and inherited susceptibility. We 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 150 patients with MASLD, 150 patients with clinically suspected MASH, and 150 age- and sex-matched healthy controls. Genotyping of GCKR rs1260326 and FGF21 rs838133 polymorphisms was performed using DNA extracted from peripheral blood samples by 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 and T allele carriers had an increased risk of MASH progression versus MASLD (AOR for TT genotype: 16.875; 95% CI: 6.339–44.921, P = 0.001), adjusted for age, sex, BMI, HOMA-IR and triglycerides level. Moreover, the TT genotype was associated with higher alanine aminotransferase levels and reduced markers of hepatic synthetic capacity. In parallel, carriers of AG genotype of FGF21 rs838133 exhibited a higher propensity for progression to MASLD (AOR: 18.622; 95% CI: 1.619-214.169, P = 0.019) and G allele 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 good discriminatory performance in differentiating MASLD from controls (AUC = 0.821) and excellent accuracy in identifying MASH among healthy individuals (AUC = 0.929). 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.