信号传导与转录激活因子3基因多态性与乙型肝炎肝硬化的相关性研究

Associations between gene polymorphisms of signal transducer and activator of transcription 3 and the susceptibility to hepatitis B virus related liver cirrhosis

旨在探讨信号传导与转录激活因子3(signal transducer and activator of transcription 3,STAT3)基因多态性与乙型肝炎病毒(hepatitis B virus,HBV)感染后肝硬化(liver cirrhosis,LC)的相关性。本研究采用病例对照研究方法,以2018年1月至2020年9月在南华大学附属长沙市中心医院就诊的243例乙型肝炎肝硬化患者(HBV-LC,实验组)与486例非肝硬化HBV感染者(non-LC,对照组)为研究对象。通过文献和生物信息数据库选定3个STAT3基因单核苷酸多态性(single nucleotide polymorphisms,SNPs)(rs4796793C>G、rs2293152C>G、rs1053004T>C),使用荧光探针实时定量PCR法(real-time fluorescent quantitative PCR,RFQ-PCR)对SNPs基因型进行检测。采用χ^(2)检验比较STAT3 SNPs各基因型在两组研究对象间的分布差异,使用SHEsis在线软件进行单倍型分析。结果显示,HBV-LC患者中HBV C基因型比例显著高于对照组(80.91%vs.70.79%,χ^(2)=7.109,P=0.008),而ALT对数值显著低于对照组(1.78±0.43 vs.1.95±0.54,t=3.801,P=0.000)。rs4796793、rs2293152和rs1053004基因型分布在HBV-LC与non-LC两组人群总体及不同性别人群间差异均无统计学意义(χ^(2)=2.610,1.505,0.586,2.653,2.685,1.583,0.351,5.388,0.339,P>0.05)。在C基因型HBV感染者中,rs1053004 CC基因型(vs.TT基因型)显著增加肝硬化的发病风险(OR=1.40,95%CI:1.03~1.91)。在HBeAg阴性HBV感染者中,rs4796793 GG基因型(vs.CC基因型)及G等位基因(vs.C等位基因)均显著增加肝硬化发病风险(OR=2.17,95%CI:1.11~4.23;OR=1.45,95%CI:1.06~1.97)。单倍型分析显示,由rs4796793、rs2293152和rs1053004构成的单倍型C-G-T在HBV-LC中的频率显著低于non-LC(27.3%vs.35.6%,χ^(2)=9.949,P=0.001)。综上,STAT3与HBV-LC的相关性在不同感染状态的HBV感染者中存在差异,携带STAT3基因单倍型rs4796793C-rs2293152G-rs1053004T的HBV感染者发生肝硬化的可能性较低。

To investigate the associations between gene polymorphisms of signal transducer and activator of transcription 3(STAT3)and liver cirrhosis(LC)after hepatitis B virus(HBV)infection.A case-control study was conducted in 243 patients with hepatitis B cirrhosis(HBV-LC,case group)and 486 HBV-infected subjects without LC(non-LC,control group)collected from January 2018 to September 2020 at the Changsha Central Hospital Affiliated to Nanhua University.Three single nucleotide polymorphisms(SNPs)of STAT3 gene,including rs4796793C>G,rs2293152C>G,and rs1053004T>C were selected through literature and biological information database,and the genotypes were detected by real-time fluorescent quantitative PCR(RFQ-PCR).The distribution differences of STAT3 SNPs genotypes between the two groups were compared using Chi-square test and haplotype analysis was conducted by Shesis online.The proportion of HBV C genotype in HBV-LC patients was significantly higher than that in the control group(80.91%vs.70.79%,χ^(2)=7.109,P=0.008),while the logarithm of ALT was significantly lower than that of the control group(1.78±0.43 vs.1.95±0.54,t=3.801,P=0.000).The genotypes distributions of rs4796793,rs2293152,and rs1053004 were not significantly different between HBV-LC and non-LC in overall analysis and stratified analysis by gender(χ^(2)=2.610,1.505,0.586,2.653,2.685,1.583,0.351,5.388,0.339,respectively,P>0.05 for each).Among the subjects infected with HBV genotype C,rs1053004 CC(vs.TT)significantly increased the risk of HBV-LC[odds ratio(OR)=1.40,95%confidence interval(CI):1.03-1.91].Among the HBV-infected subjects with HBeAg negative,rs4796793 GG genotype(vs.CC)and G allele(vs.C)significantly increased the risks of HBV-LC(OR=2.17,95%CI:1.11-4.23;OR=1.45,95%CI:1.06-1.97,respectively).Haplotypes analysis showed that the frequency of haplotype C-G-T composed of rs4796793,rs2293152,and rs1053004 was significantly lower in HBV-LC than that in the control group(non-LC)(27.3%vs.35.6%,χ^(2)=9.949,P=0.001).The correlation between STAT3 and HBV-LC is different in HBV-infected subjects with different infection status.The HBV-infected subjects carrying haplotype rs4796793C-rs2293152G-rs1053004T of STAT3 gene have significantly decreased risk of LC.