In an independent case–control cohort of severe metabolic FLD (n = 4374)32, we confirmed the presence of an interaction between female sex and PNPLA3 p.I148M variant in determining the risk of severe FLD progressing to advanced fibrosis and/or HCC (P < 0.05; Supplementary Table 1, middle panel). This evidence concerns the gene PNPLA3 and hepatocellular carcinoma.