Gatzios_2025_Liver.Int_45_e70287

BACKGROUND AND AIMS: The role of the patatin-like phospholipase domain-containing protein 3 (PNPLA3)-I148M variant in drug-induced liver injury (DILI) remains unclear. This systematic review with meta-analysis investigated whether carriage of PNPLA3 I148M may contribute to the development of hepatocellular DILI. METHODS: Scientific databases were searched up to January 31st, 2025 for studies investigating serum transaminase elevations in response to drug treatment. Studies were included if serum transaminases were elevated in at least one genetic subgroup (II/IM/MM), and the possible presence of relevant hepatocellular DILI was estimated based on Hy's law. The meta-analysis reported on any increase in transaminases compared to baseline levels. RESULTS: Eight articles covering thirteen studies with a total of 8235 patients were included in the systematic review, of which 5 studies comprising 3480 individuals were eligible for the meta-analysis. Patients were treated with small molecules (n = 602), biologicals (n = 3221), or chemotherapeutic treatments (n = 4412). None of the studies reported conclusively more occurrence of relevant hepatocellular DILI based on PNPLA3 I148M carriage. The meta-analysis suggested amplified drug-induced transaminase elevations in response to adomeglivant and basal insulin peglispro in metabolically impaired individuals with PNPLA3-IM/MM compared to PNPLA3-II (odds ratio = 1.53, 95% CI = 1.22-1.92). None of the studies were primarily designed to detect the outcome of interest. CONCLUSIONS: Low to no evidence suggests that carriage of PNPLA3 I148M confers susceptibility to develop clinically relevant hepatocellular DILI; although it may potentiate drug-induced transaminase elevations in response to adomeglivant and basal insulin peglispro in metabolically impaired individuals.