Genetic variants in ERBB4 is associated with chronic hepatitis B virus infection.
Genetic variants in ERBB4 is associated with chronic hepatitis B virus infection.
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ERBB4 的基因变异与慢性乙型肝炎病毒感染有关
DOI：
10.18632/oncotarget.6650
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发表时间：
2016-01-26
期刊：
影响因子：
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通讯作者：
Li JM
中科院分区：
文献类型：
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作者：
Liu Y;Zhou Q;He XS;Song LM;Chen L;Jiao WJ;Shen T;Yao S;Wu H;Hu ZB;Gao TM;Li JM
背景ERBB 4在肝脏疾病中的作用很少报道。本研究旨在寻找慢性B型肝炎病毒（HBV）感染的ERBB 4基因标记，并探讨ERBB 4在肝损伤中的作用。方法在1344对HBV携带者和HBV自然清除者的病例对照研究中，选择ERBB 4基因5′和3′非翻译区（UTR）的3个单核苷酸多态性和1个插入/缺失（Ins/Del）位点进行基因分型。应用荧光素酶报告系统研究Ins/Del对ERBB 4的调控作用。此外，使用ERBB 4敲除小鼠来研究ERBB 4在肝损伤中的作用。通过HPLC-MS/MS分析进行蛋白质组学定量，以鉴定肝脏特异性ERBB 4敲除小鼠和对照小鼠之间的肝脏蛋白质谱变化。结果ERBB 4 3′ UTR区rs6147150 Ins/Del和rs 1836724 T>C与慢性HBV感染风险降低相关（P分别为0.002和0.004）。此外，由于缺失let-7 c结合位点，ERBB 4基因3′ UTR缺失12 bp后，ERBB 4的表达量增加。此外，ERBB 4的缺失导致小鼠肝损伤模型中更严重的急性或慢性炎症。此外，定量蛋白质组学分析和来自癌症基因组图谱的数据显示，ACLY（从头脂肪生成的关键酶）与ERBB 4呈负相关。结论ERBB 4具有保护肝损伤的作用，其3′UTR基因变异可作为慢性HBV感染的遗传标志。
Background The role of ERBB4 in liver disease has seldom been reported. This study aims to find genetic markers at ERBB4 for chronic hepatitis B virus (HBV) infection and determine the role of ERBB4 in liver injury. Methods We selected and genotyped three single nucleotide polymorphisms and one insertion/deletion (Ins/Del) at the 5′ and 3′ untranslated region (UTR) of ERBB4 in a case-control study including 1344 pairs of HBV carriers and HBV natural clearance subjects. The luciferase reporter system was applied to study the regulative role of Ins/Del on ERBB4. Further, ERBB4 knockout mice were used to study the role of ERBB4 in liver injury. Proteomic quantification was performed by HPLC-MS/MS analysis to identify liver protein profile change between liver-specific ERBB4 knockout and control mice. Results rs6147150 Ins/Del and rs1836724 T>C at the 3′ UTR of ERBB4 were associated with reduced risk of chronic HBV infection (P = 0.002 and 0.004, respectively). Besides, the 12bp deletion at the 3′ UTR increased ERBB4 expression due to lacking let-7c binding site. In addition, loss of ERBB4 led to more severe acute or chronic inflammation in mouse liver injury models. Further, quantitative proteomic analysis and data from the cancer genome atlas revealed that ACLY, an enzyme key for de novo lipogenesis, was negatively correlated with ERBB4. Conclusions ERBB4 plays protective role from liver injury and its 3′UTR genetic variants could be genetic markers for chronic HBV infection.