Knowledge-based analyses reveal new candidate genes associated with risk of hepatitis B virus related hepatocellular carcinoma
Knowledge-based analyses reveal new candidate genes associated with risk of hepatitis B virus related hepatocellular carcinoma
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基于知识的分析揭示了与乙型肝炎病毒相关肝细胞癌风险相关的新候选基因
DOI：
10.1186/s12885-020-06842-0
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发表时间：
2020-05-11
期刊：
影响因子：
3.8
通讯作者：
Li, Miaoxin
中科院分区：
文献类型：
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作者：
Jiang, Deke;Deng, Jiaen;Li, Miaoxin
最近的全基因组关联研究（GWASs）通过对单个单核苷酸多态性（snp）的统计分析表明，乙型肝炎病毒（HBV）相关的肝细胞癌（HCC）有几个易感位点。然而，这些位点只能解释一小部分hbv相关的HCC遗传性。在目前的研究中，我们旨在通过先进的基于知识的分析来确定hbv相关HCC的其他易感位点。方法对两种hbv相关HCC的GWASs的变异水平关联值进行基于知识的分析（包括基于基因和基于基因集的关联测试）。收集了5种不同类型的基因集进行关联分析。在一个965例病例和923例对照的独立样本中，选择了基于知识的关联测试优先排序的基因内的一些snp来复制遗传关联。结果基于基因的关联分析检测到4个与hbv相关HCC风险显著或提示相关的基因：SLC39A8、GOLGA8M、SMIM31和whammp2。基于基因集的关联分析优先考虑了HCC的两个有希望的基因集，细胞周期G1/S转变和NOTCH1细胞内结构域调节转录。在基因集中，三个有希望的候选基因（CDC45， ncor1和kat2a）被进一步优先用于HCC。在肝脏特异性表达的基因中，先前与HCC相关的多个基因也被强调。然而，可能由于样本量小，没有一个被知识关联分析优先排序的基因在独立样本中被变异水平关联检验成功地复制。结论这项基于知识的综合性关联挖掘研究发现了几个与hbv相关的HCC风险相关的有前景的基因和基因集，为后续HCC发病机制的功能研究提供了便利。
BackgroundRecent 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.MethodsWe performed knowledge-based analysis (including gene- and gene-set-based association tests) on variant-level associationp-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.ResultsThe gene-based association analysis detected four genes significantly or suggestively associated with HBV-related HCC risk:SLC39A8,GOLGA8M,SMIM31, andWHAMMP2. 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,NCOR1andKAT2A) 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.ConclusionsThis 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.