真核翻译起始因子3遗传变异与HBV相关肝细胞癌发病风险的相关性

Association of genetic variants in eukaryotic translation initiation factor 3 and risk of HBV-related hepatocellular carcinoma

目的 探讨真核翻译起始因子3(eukaryotic translation initiation factor 3,eIF3)遗传变异与乙型肝炎病毒相关肝细胞癌(HBV-HCC)发病风险的关系。方法 本研究采用两阶段病例对照研究的方法,发现阶段以广西的966例HCC病例和1 003例乙型肝炎病毒表面抗原(hepatitis B surface antigen,HBsAg)阳性对照为研究对象,筛选出与HCC发病风险有关联的单核苷酸多态性(single nucleotide polymorphisms,SNP)位点,验证阶段采用上海的480例HCC病例和484例HBsAg阳性对照人群对发现阶段的阳性位点进行验证。通过单因素和多因素logistic回归分析eIF3遗传变异位点与HBV-HCC发病风险的相关性。结果本研究发现EIF3G 3′-UTR区2个具有潜在功能的SNPs(rs7401 A>G和rs23057952 A>G)与HBV-HCC的发病风险相关。其中与A等位基因携带者相比,rs7401 G等位基因携带者的HBV-HCC发病风险增加(OR=1.18,95%CI:1.02~1.38,P=0.028);而与A等位基因相比,rs2305795 G等位基因可降低HBV-HCC发病风险(OR=0.74,95%CI:0.64~0.86,P<0.001)。联合分析结果表明,携带联合风险基因型(rs7401 AG/GG基因型和rs2305795 AA基因型)的数量与HBV-HCC发病风险上升呈剂量-反应关系(Ptrend<0.001)。表达数量性状位点(expression quantitative trait loci,eQTL)分析表明,rs7401 G等位基因和rs2305795 A等位基因均与全血中EIF3G mRNA表达水平升高显著相关,并且EIF3G mRNA的表达水平在HCC癌组织中明显高于正常组织。结论EIF3G rs7401 G等位基因和EIF3G rs2305795 A等位基因均增加HBV-HCC的发病风险。

ObjectiveTo investigate the association of genetic variants in eukaryotic translation initiation factor 3(eIF3) and the risk of hepatitis B virus-related hepatocellular carcinoma(HBV-HCC).MethodsA two-stage case-control study was performed in this study. The single nucleotide polymorphisms(SNP) loci associated with HCC risk were selected in the discovery stage included 966 HCC cases and 1003 hepatitis B surface antigen(HBsAg) positive controls from Guangxi. In the validation stage, the 480 HCC cases and484 HBsAg positive controls from Shanghai were used to validate the positive loci in the discovery stage. The association between genetic variants of eIF3 and the risk of HBV-HCC was analyzed by univariable and multivariable logistic regression.ResultsThe results showed that two potential functional SNPs(rs7401 A>G and rs23057952 A>G) in 3′-UTR of EIF3G were associated with the risk of HBV-HCC. Compared with the A allele carriers, rs7401 G allele carriers had an increased risk of HBV-HCC(OR=1.18, 95%CI: 1.02-1.38, P=0.028). While, rs2305795 G allele reduced the risk of HBV-HCC compared with the A allele(OR=0.74, 95%CI: 0.64-0.86,P<0.001). Combined analysis showed a dose-response manner between the number of unfavorable genotypes(rs7401 AG/GG genotypes and rs2305795 AA genotype) and the increased risk of HBV-HCC(Ptrend<0.001). Expression quantitative trait loci(eQTL) analysis revealed that both rs7401 G allele and rs2305795 A allele were significantly associated with increased EIF3G mRNA expression level, which were significantly higher in HCC tissues than in normal tissues.Conclusions EIF3Grs7401 G allele and EIF3G rs2305795 A allele can increase the risk of HBV-HCC.