| Description: |
INTRODUCTION AND OBJECTIVES: Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, MASH, are closely related to obesity and lifestyle. From previous studies, MASLD is also known for its strong genetic background. This study aimed to investigate the association between previously reported genetic polymorphisms of MASLD/MASH and clinical outcomes in an elderly Western European population. PATIENTS AND METHODS: We performed an analysis of 5,244 participants (mean age 75.3 years) from the PROSPER cohort study who were followed for 3.2 years. FIB-4 scores were calculated using age, AST, ALT, and platelet count, applying age-specific cutoffs. Thirty MASLD/MASH-associated SNPs, previously identified in GWAS analyses, were evaluated for their association with FIB4 scores. For SNPs showing significant differences in FIB-4 score across genotypes, associations with clinical outcomes and all-cause mortality were assessed using Cox proportional hazards regression models, adjusted for relevant clinical covariates. RESULTS: Five SNPs were significantly associated with FIB-4 scores. PNPLA3_rs738409 and SAMM50_rs3761472 showed higher FIB-4 scores in mutant homozygotes, while SLC39A8_rs13107325, TRIB1_rs2954021, and ANPEP_rs7168849 showed the opposite trend. Despite statistical significance, absolute FIB-4 scores remained within ranges typically associated with low fibrosis risk. TRIB1_rs2954021 was linked to stroke, SLC39A8_rs13107325 to myocardial infarction and ANPEP_rs7168849 to all-cause and cancer-related mortality. No significant associations were observed for PNPLA3_rs738409 or SAMM50_rs3761472 with cardiovascular and mortality outcomes. CONCLUSIONS: Our findings reveal that specific MASLD/MASH-associated genetic variants influence FIB-4 scores and are linked to cardiovascular and mortality outcomes in an elderly population. These results suggest that liver fibrosis may reflect not only hepatic injury, but also broader systemic vulnerability driven by genetic predisposition. ... |