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Page 4 of 12 Tai et al. Hepatoma Res 2020;6:74 I http://dx.doi.org/10.20517/2394-5079.2020.54

Soon after HBV infection, part of the HBV genome can be integrated into the host genome. The
+
mechanism of HBV integration is not fully understood. From the in vitro study done using the Na -
taurocholate co-transporting polypeptide (NTCP) transfected hepatoma cell line, HBV integration can
[33]
be detected randomly in the host genome shortly after infection . This observation implies that HBV
integration is independent of immune-related inflammation. These HBV integrations are mostly harmless
but may produce genomic instability. After decades, some of the integrations may become more prominent.
In the presence of additional factors, such as inflammation, HBV mutations, or environmental carcinogens,
a segment of the hepatocytes carrying HBV integrations may become clonal and develop into HCC. Several
integration hot sites, including TERT, KMT2B, DDX11L1, CCNE1, and CCNA2, can be found more
[34]
frequently in HCC than in non-HCC tissues , while FN1 is commonly found in non-tumour tissues. A
[35]
prolonged HBeAg phase and high viral load carry a higher frequency of HBV integrations .
HBV mutants and host interaction
The wild-type HBV genome and its proteins are not directly cytopathic. Host immune responses and
inflammation are induced to clear HBV during the second to fourth decades of life in East Asians. If the
HBV immune clearance process is unsuccessful and prolonged, complicated HBV mutations may develop
and escape immune surveillance. Through repeat necroinflammation, several mutation hot spots in the
EnhII (C1653T)/BCP(A1762T/G1764A, T1753V)/PC(G1896A) regions were found more frequently in
[36]
HCC . In addition, some of the pre-S/S mutations or truncations may become directly cytopathic and/or
carcinogenic .
[37]
HLA SNPS IN RELATION TO HBV INFECTION AND HEPATOCARCINOGENESIS
Global allele frequency of HBV-related SNPs in HLA loci
Based on GWAS studies, HLA-DP and -DQ loci are associated with persistent HBV infection. These SNPs
have been reported quite consistently from different centres in East Asia.

To understand the global allele frequency of the HBV-related SNPs, we collected data from the 1000
Genomes Project, with the results listed in Table 1. Although HBsAg prevalence in East Asians is as high as
in Africans, the two populations did not show similar allele frequencies on these SNPs. In general, the allele
frequencies of these SNPs are significantly different between East Asians and other global populations.
Only 5/19 (26.3%) SNPs showed similar allele frequencies between populations from East Asia and Africa
[Table 1]. Therefore, these HBV-related SNPs in the HLA-DP and -DQ loci may not completely explain the
high prevalence of HBsAg in Africa.

[24]
We suspect that the evolution of these SNPs may be related to human migration . The Indo-China
peninsula and southern China are mountainous and forested areas. Such geographic environments are
associated with a great diversity of microorganisms, insects, plants, and animals. People who can survive
in this milieu may need some adjustments to their immunity, lest they succumb to a cytokine storm after
exposure to multiple unfamiliar microorganisms. Because of modified antigen presentation resulting
from HLA-DP and -DQ loci, immunity may be decreased or separated into several stages to avoid the
development of cytokine storm. Unfortunately, such immunity may also allow HBV infection to become
chronic and persistent. HBV clearance is delayed, but clearance may finally occur several decades later. As
a matter of fact, only a minority of HBsAg carriers die of acute or chronic liver disease, and around half of
[7]
chronic HBsAg carriers clear HBsAg by 80 years of age .
Mechanism of persistent HBV infection in HLA-DP and- DQ SNPs
Both rs3077 and rs9277535 were identified by GWAS to be associated with persistent HBV infection in
[18]
Japanese patients . Allele A of rs3077 and rs9277535 are associated with a higher mRNA expression than
allele G . The prevalence of the A allele is lower in East Asia compared to other geographic areas [Table 1].
[38]