Knowledge-based analyses reveal new candidate genes associated with risk of hepatitis B virus related hepatocellular carcinoma
Deke Jiang,
Jiaen Deng,
Changzheng Dong,
Xiaopin Ma,
Qianyi Xiao,
Bin Zhou,
Chou Yang,
Lin Wei,
Carly Conran,
S. Lilly Zheng,
Irene Oi-lin Ng,
Long Yu,
Jianfeng Xu,
Pak C. Sham,
Xiaolong Qi,
Jinlin Hou,
Yuan Ji,
Guangwen Cao,
Miaoxin Li
Affiliations
Deke Jiang
State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University
Jiaen Deng
Department of Psychiatry, the University of Hong Kong
Changzheng Dong
Ningbo University School of Medicine
Xiaopin Ma
State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University
Qianyi Xiao
Center for Genomic Translational Medicine and Prevention, School of Public Health, Fudan University
Bin Zhou
State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University
Chou Yang
State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University
Lin Wei
Program of Computational Genomics & Medicine, NorthShore University HealthSystem
Carly Conran
Program for Personalized Cancer Care, NorthShore University HealthSystem, Pritzker School of Medicine, University of Chicago
S. Lilly Zheng
Program of Computational Genomics & Medicine, NorthShore University HealthSystem
Irene Oi-lin Ng
Department of Pathology, the University of Hong Kong
Long Yu
State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University
Jianfeng Xu
Program of Computational Genomics & Medicine, NorthShore University HealthSystem
Pak C. Sham
The Centre for Genomic Sciences, the University of Hong Kong
Xiaolong Qi
State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University
Jinlin Hou
State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University
Yuan Ji
Department of Public Health Sciences, University of Chicago
Guangwen Cao
Department of Epidemiology, Second Military Medical University
Miaoxin Li
Department of Psychiatry, the University of Hong Kong
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 knowledge-based analysis. Methods We performed knowledge-based analysis (including gene- and gene-set-based association tests) on variant-level association p-values from two existing GWASs of HBV-related HCC. Five different types of gene-sets were collected for the association analysis. A number of SNPs within the gene prioritized by the knowledge-based association tests were selected to replicate genetic associations in an independent sample of 965 cases and 923 controls. Results The gene-based association analysis detected four genes significantly or suggestively associated with HBV-related HCC risk: SLC39A8, GOLGA8M, SMIM31, and WHAMMP2. The gene-set-based association analysis prioritized two promising gene sets for HCC, cell cycle G1/S transition and NOTCH1 intracellular domain regulates transcription. Within the gene sets, three promising candidate genes (CDC45, NCOR1 and KAT2A) were further prioritized for HCC. Among genes of liver-specific expression, multiple genes previously implicated in HCC were also highlighted. However, probably due to small sample size, none of the genes prioritized by the knowledge-based association analyses were successfully replicated by variant-level association test in the independent sample. Conclusions This comprehensive knowledge-based association mining study suggested several promising genes and gene-sets associated with HBV-related HCC risks, which would facilitate follow-up functional studies on the pathogenic mechanism of HCC.
