Host genetic factors affecting hepatitis B infection outcomes: Insights from genome-wide association studies

Abstract

The clinical outcome of hepatitis B virus (HBV) infection depends on the success or failure of the immune responses to HBV, and varies widely among individuals, ranging from asymptomatic self-limited infection, inactive carrier state, chronic hepatitis, cirrhosis, hepatocellular carcinoma, to liver failure, depending on the success or failure of immune response to HBV. Genome-wide association studies (GWAS) identified key genetic factors influencing the pathogenesis of HBV-related traits. In this review, we discuss GWAS for persistence of HBV infection, antibody response to hepatitis B vaccine, and HBV-related advanced liver diseases. HBV persistence is associated with multiple genes with diverse roles in immune mechanisms. The strongest associations are found within the classical human leukocyte antigen (HLA) genes, highlighting the central role of antigen presentation in the immune response to HBV. Associated variants affect both epitope binding specificities and expression levels of HLA molecules. Several other susceptibility genes regulate the magnitude of adaptive immune responses, determining immunity vs tolerance. HBV persistence and nonresponse to vaccine share the same risk variants, implying overlapping genetic bases. On the other hand, the risk variants for HBV-related advanced liver diseases are largely different, suggesting different host-virus dynamics in acute vs chronic HBV infections. The findings of these GWAS are likely to pave the way for developing more effective preventive and therapeutic interventions by personalizing the management of HBV infection.

Editorial: genome‐wide association for developing chronic hepatitis B—authors’ reply

“…They initiate immune responses by presenting extracellular antigens to CD4 + T cells. The single nucleotide variants near the HLA region identified in previous genome‐wide association studies (GWASs) 4 were consistently validated in our study, demonstrating the relevance of the polymorphic region to chronic HBV infection. By taking advantage of the powerful HLA imputation algorithm, we could comprehensively examine the associations between HLA genotypes and chronic HBV infection.…”

Editorial: genome‐wide association studies for developing chronic hepatitis B

“…These findings are consistent with previous reports (Table 1). 1‐3,5 The HLA alleles in the most recent paper had various binding affinities to the predicted epitopes derived from HBV nucleocapsid protein 3 . Interestingly, these allele frequencies were positively correlated with global hepatitis B surface antigen seroprevalence.…”

“…With the unbiased approach of genome‐wide association studies (GWAS), single‐nucleotide polymorphisms (SNPs) mainly related to HLA class II (but also HLA‐C) alleles related to chronicity have been identified (Table 1). 1,2 Since antigens are presented to T lymphocytes in the context of HLA, polymorphisms in HLA can alter specificity and strength of HBV antigen binding, affecting T lymphocyte‐mediated immunity to HBV. In addition, several associations with chronicity of HBV outside classic HLA alleles (some within and some outside HLA) have been identified.…”

“…In addition, several associations with chronicity of HBV outside classic HLA alleles (some within and some outside HLA) have been identified. All these SNPs concern immunological functions, such as the polymorphisms in CFB representing a variant in complement factor B 1,2 …”

IPS-1 polymorphisms in regulating interferon response in HBV infection

“…IFN inhibits HBV replication via the MDA5/IPS-1 pathway, but patients display different prognosis to HBV infection. Studies on genetics determine susceptibility of HBV infection and subsequent chronicity has been well documented in families of segregation analysis or twin studies (15,16). SNP of IL28B is responsible for the therapeutic outcomes following PEG-IFN plus ribavirin treatment in chronic viral hepatitis C (CHC) (17).…”