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Page 2 of 12 Tai et al. Hepatoma Res 2020;6:74 I http://dx.doi.org/10.20517/2394-5079.2020.54

Keywords: Genetic polymorphism, genome-wide associated studies, hepatitis B virus, hepatocellular carcinoma

INTRODUCTION
Hepatitis B is a global disease that results in an increased risk of liver cirrhosis and hepatocellular
[1,2]
carcinoma . A strong familial clustering of chronic hepatitis B carriers and hepatocellular carcinomas
[3-6]
(HCC) has been well-reported . This could be related to the high intrafamilial spread of hepatitis B virus
[4]
(HBV) infection. Infection of HBV in the early stage of life will result in chronic persistent infection .
Throughout the course of this disease, intermittent relapsing liver necroinflammation will occur. This
process is a defensive response to eliminate HBV replication and/or clear the virus. In general, by 80 years
of age, half of chronic hepatitis B carriers will have suppressed HBV replication and cleared hepatitis B
[7]
surface antigens (HBsAg) .
However, some patients may develop liver cirrhosis as a result of repeated liver inflammation and
[8]
fibrogenesis . Liver necroinflammation can induce chromosomal damage , and HBV is able to integrate
[9]
[10]
into the human genome . Such an injury to the host genome can induce chromosomal instability and
promote hepatocarcinogenesis. Genetic factors associated with HCC have been considered because of
its familial tendency. Many candidate genes and genome-wide associated studies (GWAS) have revealed
nearly one hundred genes to be associated with chronic persistent infection or hepatocarcinogenesis [11-14] .
Previous extensive and elegant meta-analysis reports have addressed these issues. However, not all of these
HBV/HCC related genes have been confirmed and replicated by subsequent studies, demonstrating the
difficulties in sorting HCC-associated genes. This is partly due to the fact that HBV-host interactions are
not simply a genetic problem, as well as the fact that there are differences in the genetic backgrounds of
study populations.

Therefore, in this study, we shall try to understand HBV-related single nucleotide polymorphisms (SNPs)
by performing correlations between genetic backgrounds and two well-known epidemiological datasets.
[15]
The genetic backgrounds will be obtained from the 1000 Genomes Project (http://www.1000genomes.org/) .
Epidemiological concerns about a higher prevalence of HBsAg in southern compared to Northeastern
[16]
Asia will be used in the evaluation for persistent HBV infection . A higher prevalence of HCC in West
Africa compared to East Africa will also be used for evaluation of hepatocarcinogenesis (World Health
Organization, http://gco.iarc.fr/today). With these viewpoints, we may obtain additional information
independent of the observations in reported studies about HBV-related genetic polymorphisms.

CHRONIC PERSISTENT HBV INFECTION
Hepatocarcinogenesis in chronic HBV infection is not a purely genetic disease; it depends on host and
virus interactions. Persistent HBV infection is the first stage toward hepatocarcinogenesis.

HBV clearance
When humans are exposed to HBV, either acute hepatitis with spontaneous viral clearance or chronic
persistent infection may develop [Figure 1]. Both the timing and transmission route of infection are
important in persistent infections. Individuals who are infected in the early stages of life and via vertical
[4]
transmission are more likely to develop persistent infection . In GWAS studies, HLA-DP and -DQ have
been shown to consistently be associated with persistent HBV infection in East Asians [17-23] . However, such
[24]
high-risk alleles are relatively rare in Africans . Therefore, HBV infection elicited in the early stages of life
remains an important mechanism of persistent HBV infection. It is independent of genetic polymorphisms
in the HLA-DP and -DQ loci.