The association between the PNPLA3 variant I148M and the risk of HCC development has been robustly validated in patients with NAFLD [137, 138], and it has been estimated that the homozygous carriers of the p.148M mutation carry a 12-fold increased HCC risk as compared to p.I148 homozygotes [139]. This evidence concerns the gene PNPLA3 and hepatocellular carcinoma.