Oncotarget

Research Papers:

Genetic variants in ERBB4 is associated with chronic hepatitis B virus infection

Yao Liu, Qun Zhou, Xiao-Shun He, Li-Ming Song, Lin Chen, Wei-Juan Jiao, Tong Shen, Su Yao, Hua Wu, Zhi-Bin Hu, Tian-Ming Gao and Jian-Ming Li _

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Oncotarget. 2016; 7:4981-4992. https://doi.org/10.18632/oncotarget.6650

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Abstract

Yao Liu1,2,*, Qun Zhou1,*, Xiao-Shun He1, Li-Ming Song3, Lin Chen3, Wei-Juan Jiao1, Tong Shen1, Su Yao3, Hua Wu1, Zhi-Bin Hu2, Tian-Ming Gao4, Jian-Ming Li1,3

1Department of Pathology, Medical College of Soochow University, Suzhou 215123, People’s Republic of China

2Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing 211166, People’s Republic of China

3Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People’s Republic of China

4Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, People’s Republic of China

*These authors have contributed equally to this work

Correspondence to:

Jian-Ming Li, e-mail: [email protected]

Tian-Ming Gao, e-mail: [email protected]

Zhi-Bin Hu, e-mail: [email protected]

Keywords: ERBB4, hepatitis B virus, polymorphism, inflammation

Received: August 13, 2015     Accepted: December 05, 2015     Published: December 18, 2015

ABSTRACT

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.


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