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

Background & Aims The rs738409 C>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. Primary outcome was liver-related events(LRE); 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 LRE(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 LRE(HR 1.57, 95%CI 1.12-2.19), but not of HCC. PNPLA3 genotypes did not affect the risk of major cardiovascular events, extrahepatic cancers, or all-cause mortality. Conclusions 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 liver-related events and HCC who might benefit from closer monitoring.