In this study, we used an integrative genomic strategy to demonstrated that 1) a simple but effective approach can be applied to identify new HCC-related genes and variants by integrating ChIP-seq data, genome mapping and dbSNP database; 2) SERPINA6-rs1998056 is significantly associated with female HCC risk suggested by the subsequent case-control study; and 3) results of qPCR using target tissues further supported the functional effect of this variant. This evidence concerns the gene SERPINA6 and hepatocellular carcinoma.