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- 2009-10-5
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- 2022-12-28
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PS-050
Integrated analyses of both human and HBV genome to predict
HCC Development
Masaya Sugiyama1, Nishida Nao1, Katsushi Tokunaga2,
Mizokami Masashi1. 1National Center for Global Health and Medicine,
Ichikawa, Japan; 2The University of Tokyo, Tokyo, Japan
Email: [email protected]
Background and aims: Hepatitis B virus (HBV) infection is a major
cause of hepatocellular carcinoma (HCC). Clinical outcomes are
induced by interactions between viral and host factor. Especially, a
prediction marker of HCC development provides great benefits forclinician and patients. In the present study, we determined a host
genetic factor associated with HBV-derived HCC, and discovered viral
genetic factors corresponding to the host genetic variation.
Method: Total 2, 996 individualswere enrolled from10 hospitals, 408
chronic hepatitis B (CHB) patients, 307 HBV-derived HCC patients,
and 2, 281 healthy volunteer (HV). Human genetic data were
obtained from SNPs array and Luminex method for HLA genotype.
These genetic datawere filled up by imputation techniques. For viral
genome analysis, HBV DNAwas extracted from serum of CHB or HCC
patients and was prepared for next-generation sequencing (NGS). All
sequence reads were converted from nucleic acid into amino acid
(AA) sequences. Multiple comparisons were counteracted by statistical
method.
Results: By genome-wide association study using SNPs and HLA
genotype, HLA-DPB1*02:01 was an independent protection factor
against HCC development (p < 4.53x10-9, OR = 0.53). HLADPB1*
04:01 was statistically associated with the protection against
CHB establishment (p < 6.49x10-6, OR = 0.31). Next, we focused on
viral genomic factor related with HCC development. Patients with
HLA-DPB1*02:01 homozygote were divided into HCC and non-HCC
group with age-, sex-, HBV genotype-matched condition. The half of
the samples was used for test set. AAvariations of HBV protein were
restricted to particular patterns in PreS/S protein in the HCC group
with the HLA-DPB1*02:01. The ratio of S166 in CHB and HCC was
51.5% and 0%, respectively (p < 0.05). However, the ratio of L166 in
CHB and HCC was 34.3% and 99.4%, respectively (p < 0.05). The
mutationwas confirmed using validation sample set. S166L mutation
was also associated with HCC development (p < 0.02, OR = 18.2). In
addition, we determined the effect of S166L mutation in HLADPB1*
02:01 heterozygote with or without HCC. S166L mutation was
statistically associated with HCC patients with the heterozygotes (p <
0.05, OR = 1.6). But, S166L mutation in PreS/S didn’t change AA
sequence in HBV polymerase.
Conclusion: We detected host and viral genetic factors related with
clinical outcomes. Hepatitis B patients with both HLA-DPB1*02:01
allele and S166 in PreS/S were low risk for HCC development.
However, when they had L166 mutation, they had high risk for HCC. A
specific AA change in the HBV antigen could affect HCC development
by interaction change between host and virus. This is a proof of
concept study in order to predict a prognosis using genomic data in
hepatitis B.
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发表于 2019-3-31 10:26