Abstract
Three genome-wide association studies (GWAS) have been conducted on the genetic susceptibility of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), two of which consistently identified tagging single nucleotide polymorphisms (SNPs) around HLA-DQ/DR. In contrast, large multi-centre association studies between HBV genotype, mutations and the risk of HCC are relatively rare, and their interactions with host variants are even less. We performed a multi-centre study of 1,507 HBV-related HCC cases and 1,560 HBV persistent carriers as controls to evaluate the effects of HBV genotype, mutations, GWAS-identified HLA-DQ/DR SNPs (rs9272105 and rs9275319) and their interactions on HCC risk. We found HBV genotype C was more frequent in HBV-related HCC. And 11 HBV hotspot mutations were independently and significantly associated with HCC risk. We also detected significant interactions of rs9272105 with both the HBV genotype and mutations. Through stepwise regression analysis, HBV genotype, the 11 mutations, HLA-DQ/DR SNPs, and the interaction of rs9272105 with mutation A1752G were all entered into the HCC prediction model, and the area under the curve for the panel including the HLA-DQ/DR SNPs, HBV genotype and mutations was 0.840. The HBV genotype, the mutations and the HLA-DQ/DR SNPs may serve as biomarkers for the surveillance of HBV persistent carriers.
Highlights
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide, with the incidence on the rise both in developed and developing countries[1,2]
For the panel including two single nucleotide polymorphism (SNP), hepatitis B virus (HBV) genotype and mutations, the Hosmer-Lemeshow χ 2 (8 degrees of freedom) was 11.64 (P = 0.168), giving no cause for concern over model fit or calibration. In this large multi-centre study, we found that HBV genotype C and subgenotype C2 were the risk factors for HCC, and 11 HBV mutations were found to be significantly associated with HCC risk
The HBV carriers who infected with HBV genotype C and carrying the rs9272105 AA genotype, rs9275319 AA genotype and risky nucleotide of the 11 HBV mutations had a relatively high HCC risk, which was useful in screening of high-risk groups of HCC and needed to be validated in further prospective studies
Summary
Selected characteristics of the 1,507 HBV-related HCC patients and the 1,560 HBV persistent carriers are described in Supplementary Table S2. There were similar distributions of age and gender between the HCC patients and the HBV persistent carriers (P = 0.835 and 0.687, respectively). Similar distributions of age and gender were seen between the cases and controls of the additional sample set from Xi’an (Supplementary Table S3). Among the participants of this study, the HBV genotypes B, C, BC (coinfection) and D and the subgenotypes B2, C1, C2, B2C1, B2C2, B2C1C2 and C1C2 were identified through nested multiplex PCR and sequencing. All the amplicons were of the size expected for each genotype and subgenotype, as shown in Supplementary Fig. S1. The sequencing peak chart of all the genotypes and subgenotypes is shown in Supplementary Fig. S2.
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