Gonzalez-Aldaco_2026_Int.J.Mol.Sci_27_

Genetic variation in PNPLA3 influences liver fat accumulation and hepatocellular injury in various liver diseases. However, the role of PNPLA3 intronic polymorphisms in hepatic damage among hepatitis C virus (HCV) patients remains unclear. This study aims to investigate the association of three intronic PNPLA3 polymorphisms (rs4823173, rs2896019, and rs2281135) with liver injury in HCV-infected patients with spontaneous HCV clearance (SC) and chronic hepatitis C (CHC). A total of 218 HCV-positive individuals were classified into SC (n = 64) or CHC (n = 154) groups. PNPLA3 genotypes were determined by qPCR using TaqMan probes and liver damage through serum markers, noninvasive index, and liver stiffness. Among SC patients, the genotypes AA-rs4823173, GG-rs2896019, and AA-rs2281135 were associated with higher AST, ALT, and APRI, as well as decreased platelet counts, compared with patients homozygous for the non-risk genotypes (p < 0.05). No associations were found in CHC patients. The three polymorphisms were in perfect linkage disequilibrium (r(2) = 1). The risk haplotype AGA was associated with higher AST and ALT, as well as lower platelet counts (p < 0.05) in SC patients. PNPLA3 intronic polymorphisms and their association with serum liver injury markers could help identify hepatic injury in HCV-negative patients.