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

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.