PNPLA3 polymorphisms and risk of hepatic and extrahepatic outcomes in MASLD: A meta-analysis of observational studies

Background & aims: The rs738409C>G polymorphism in the patatin-like phospholipase domain-containing protein 3 gene (PNPLA3 I148M variant) contributes to the largest fraction of metabolic dysfunction-associated steatotic liver disease (MASLD) heritability. However, its prognostic impact on long-term clinical outcomes related to MASLD remains incompletely characterized. We performed a meta-analysis of observational studies to quantify the impact of PNPLA3 polymorphisms on the risk of developing hepatic and extrahepatic outcomes in MASLD. Methods: We systematically searched PubMed, Scopus, and Cochrane Central for observational studies evaluating PNPLA3 polymorphisms and clinical outcomes in MASLD. The primary outcome was liver-related events (LREs); secondary outcomes included new-onset hepatocellular carcinoma (HCC), liver-related mortality, cardiovascular events, extrahepatic cancers, and all-cause mortality. We compared homozygous risk-allele carriers (GG) and heterozygous carriers (CG) with wild-type homozygous (CC) individuals using random-effects genotypic models. The study was registered on PROSPERO (CRD#420251176886). Results: Twenty-one observational longitudinal studies, including 232,033 adult individuals with MASLD (median follow-up: 7.2 years), were analysed. Individuals with the GG genotype had significantly higher risks of incident LREs (hazard ratio [HR] 2.87, 95% CI 1.92-4.27) and HCC (HR 2.54, 95% CI 1.86-3.47) compared with the CC genotype. CG carriers also had an increased risk of LREs (HR 1.57, 95% CI 1.12-2.19), but not of HCC. PNPLA3 genotypes were not associated with the risk of major cardiovascular events, extrahepatic cancers, or all-cause mortality. Conclusions: The PNPLA3 I148M polymorphism confers dose-dependent increases in LRE and HCC risk in MASLD, with liver-specific rather than systemic effects. These findings suggest that PNPLA3 genotyping may inform risk stratification strategies in MASLD, particularly for identifying individuals at higher risk of LREs and HCC who might benefit from closer monitoring. Impact and implications: International consensus has prioritised patient education and awareness as a key research domain in MASLD, yet quantitative evidence from patients with an established diagnosis remains scarce, particularly in Europe. In 460 Italian adults with physician-diagnosed MASLD we found pervasive knowledge gaps - including the failure to recognise diabetes as a risk factor and the belief that normal transaminases exclude progressive disease - a wide gap between lifestyle counselling and actual adherence, largely self-prescribed supplement use, partly guideline-discordant pharmacotherapy, and educational attainment as the principal determinant of every cognitive domain. These results are relevant to hepatologists, primary care physicians, patient associations and policymakers, because such misconceptions may delay referral, weaken adherence, and hinder equitable access to newly available therapies such as resmetirom and incretin-based agents. The validated five-domain instrument provides a reproducible tool to profile patients, tailor education to health literacy level and monitor its effect; however, since participants were recruited through a patient association and reported data themselves without fibrosis staging, these estimates probably represent a best-case scenario of awareness and require confirmation in unselected clinical cohorts.