Host Genetic Determinants of Hepatitis B Virus Infection

Abstract

Chronic hepatitis B virus (HBV) infection is still a major health problem worldwide. Recently, a great number of genetic studies based on single nucleotide polymorphisms (SNPs) and genome-wide association studies have been performed to search for host determinants of the development of chronic HBV infection, clinical outcomes, therapeutic efficacy, and responses to hepatitis B vaccines, with a focus on human leukocyte antigens (HLA), cytokine genes, and toll-like receptors. In addition to SNPs, gene insertions/deletions and copy number variants are associated with infection. However, conflicting results have been obtained. In the present review, we summarize the current state of research on host genetic factors and chronic HBV infection, its clinical type, therapies, and hepatitis B vaccine responses and classify published results according to their reliability. The potential roles of host genetic determinants of chronic HBV infection identified in these studies and their clinical significance are discussed. In particular, HLAs were relevant for HBV infection and pathogenesis. Finally, we highlight the need for additional studies with large sample sizes, well-matched study designs, appropriate statistical methods, and validation in multiple populations to improve the treatment of HBV infection.

Keywords: genetic determinants; genome-wide association study; hepatitis B virus; human leukocyte antigen; single nucleotide polymorphism; susceptibility gene.

Figure 1

Natural history of chronic hepatitis B virus (HBV) infection, interventions, and clinical outcomes. The natural history of HBV infection is typically classified into four clinical states: HBeAg+ chronic HBV infection, HBeAg+ chronic hepatitis, HBeAg– chronic HBV infection, and HBeAg− chronic hepatitis according to the guideline of European Association for the Study of the Liver (EASL). Patients with chronic HBV infection do not necessarily experience all states. HBV vaccine and/or HBIg injection may prevent HBV transmission; during HBeAg+ chronic hepatitis, treatment with nucleos(t)ide analogs (NUCs) or interferon-alpha (IFN-α) may suppress HBV replication, slow disease progression, and reduce the risk of cirrhosis and hepatocellular carcinoma; HBV reactivation may occur during HBeAg– chronic HBV infection in patients with HBsAg and/or anti-HBc positive after chemotherapy or immunosuppression. The course of HBV infection and disease progression are variable, indicating that host genetic determinants play an important role in HBV infection.

Figure 2

Host genetic determinants of HBV infection. The outcomes of HBV infection are highly diverse, including acute hepatitis, self-limiting recovery, chronic hepatitis, cirrhosis, liver cancer, and liver failure. The disease outcome is related to viral, environmental, and host factors. This map shows important host genes that may be associated with clinical outcomes of HBV infection or Hepatitis B vaccination. Black boxes show the relevant genes identified, in which the bold letter indicates a high degree of correlation and the italic indicates a possible correlation to clinical features of HBV infection.

Figure 3

Host genes and immune mechanisms involved in HBV infection. Host innate and adaptive immunity represent the major determinants of the outcome of HBV infection. The genetic diversity of many genes related to innate and adaptive immunity have been found to be relevant for hepatitis B vaccination, HBV infection, and antiviral therapy. Blue letters show the relevant genes identified in the previous studies. The bold and italic letters indicate a high degree or potential correlation of the indicated host factors to clinical features of HBV infection.