Abstract
Background : Recent genome-wide association studies (GWASs) have suggested several susceptibility loci of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) by statistical analysis at individual single-nucleotide polymorphisms (SNPs). However, these loci only explain a small fraction of HBV-related HCC heritability. In the present study, we aimed to identify additional susceptibility loci of HBV-related HCC using advanced gene- and gene-set-based association tests.Methods: We performed a meta-analysis of two existing GWASs of HBV-related HCC, based on which a series of association analyses at genes and multiple gene sets curated according to current knowledge were carried out for prioritizing potential risk genes. A series of prioritized SNPs were selected to replicate genetic associations in an independent sample of 965 cases and 923 controls.Results: The gene-based association analysis suggested that five genes are significantly associated with HBV-related HCC risk: RNY4, GOLGA8M, LINC01207, WHAMMP2 and SLC39A8. Through gene-set-based association analysis, we found that the genes in systemic lupus erythematosus pathway may be relevant to development of HBV-related HCC. Three previously reported genes, NAT2, GSTA1 and GSTA2, were also highlighted to be susceptibility genes of HBV-related HCC when genes were stratified in a liver-specific expression set. However, probably due to small sample size, none of the genes prioritized by knowledge-based association analyses are successfully replicated in an independent sample.Conclusions: This comprehensive knowledge-based association mining study suggested several promising genes significantly associated with HBV-related HCC risk. More experiments or larger samples are needed to validate their contribution to the pathogenic mechanism of HCC.