TF-rs1049296 C>T Variant Modifies the Association between Hepatic Iron Stores and Liver Fibrosis in Metabolic Dysfunction-associated Steatotic Liver Disease

Background and Aims: Hepatic iron deposition (HID) in the reticuloendothelial system (RES) is associated with histological severity in metabolic dysfunction-associated steatotic liver disease (MASLD). This study aimed to assess the interaction between the transferrin (TF)-rs1049296 C>T variant and HID patterns on the risk of significant liver fibrosis in MASLD. Methods: We analyzed 406 adults with liver biopsy-confirmed MASLD. HID was categorized as hepatocellular, RES, or mixed, based on Perl's iron staining. The association between iron-related genetic variants and significant liver fibrosis (fibrosis stage >= F2) was analyzed, focusing on the interactions between single-nucleotide polymorphism genotypes and iron deposition patterns. Multivariable logistic regression analysis was used to adjust for potential confounders. Results: HID was detected in 271 (66.7%) patients, with hepatocellular, RES, and mixed patterns accounting for 11.1%, 18.0%, and 37.7%, respectively. A significant interaction was observed between HID and the TF-rs1049296 genotype (P-interaction = 0.035). In multivariable analysis, male sex, hypertension, severe lobular inflammation, and mixed hepatocellular/RES iron deposition were independent predictors of significant liver fibrosis. RES deposition markedly increased the risk of significant liver fibrosis (adjusted odds ratio: 6.65; 95% confidence interval: 1.84-23.97, p < 0.05), particularly in men with isolated RES iron deposition (adjusted odds ratio: 5.26; 95% confidence interval: 1.21-22.81, p < 0.05). Conclusions: The TF-rs1049296 T allele interacts with RES iron deposition to identify a MASLD subpopulation at elevated risk of progressive liver disease, providing opportunities for refined risk stratification and personalized management.