JHEP Rep. 2026 Jun 5:101918. doi: 10.1016/j.jhepr.2026.101918. Online ahead of print.
ABSTRACT
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.
PMID:42250763 | DOI:10.1016/j.jhepr.2026.101918