Abstract
Genetic variants in zinc ribbon domain-containing 1 antisense RNA 1 (ZNRD1-AS1) have been reported to be associated with development of hepatocellular carcinoma (HCC). We sought to determine the influences of ZNRD1-AS1 polymorphisms and their interactions with Hepatitis B virus (HBV) genotypes on the risk of HCC. In this study, we conducted a large population case-control study with 1,507 HBV-related HCC cases and 1,560 HBV persistent carriers. Three single-nucleotide polymorphisms (SNPs) in ZNRD1-AS1 (rs3757328, rs6940552 and rs9261204) were genotyped using a TaqMan allelic discrimination assay, and the HBV genotypes were identified by multiplex PCR. We found consistently significant associations between the ZNRD1-AS1 rs6940552 and rs9261204 SNPs with an increased risk of HCC (additive genetic model: adjusted OR = 1.16, 95% CI = 1.03-1.32 for rs6940552; adjusted OR =1.20, 95% CI = 1.06-1.35 for rs9261204) and found a borderline association between rs3757328 and HCC risk. Besides, we observed a dose-dependent relationship between increasing numbers of variant alleles of the SNPs and HCC risk (P for trend <0.001). Moreover, we observed a stronger combined effect of the three SNPs on HCC risk among the subjects infected with non-B genotype HBV (adjusted OR = 1.26, 95% CI = 1.05-1.50) compared with HBV B-related genotypes (adjusted OR = 0.89, 95% CI = 0.69-1.15; P= 0.029 for heterogeneity test). We also found that a multiplicative interaction between the variant alleles and the HBV genotype significantly affected HCC susceptibility (P = 0.030). Together, these results indicate that ZNRD1-AS1 may influence HCC risk accompanied by HBV genotypes.
Highlights
Hepatocellular carcinoma (HCC) poses a substantial threat to public health, in less developed regions [1]
We found consistently significant associations between the Zinc ribbon domain-containing 1 (ZNRD1)-AS1 rs6940552 and rs9261204 single-nucleotide polymorphisms (SNPs) with an increased risk of hepatocellular carcinoma (HCC) and found a borderline association between rs3757328 and HCC risk
These results indicate that ZNRD1-AS1 may influence HCC risk accompanied by Hepatitis B virus (HBV) genotypes
Summary
Hepatocellular carcinoma (HCC) poses a substantial threat to public health, in less developed regions [1]. More than 50% of HCC cases occur in China [2]. It has been estimated that 75–85% of HCC cases in China are attributable to chronic HBV infection. Only a minority of chronic HBV carriers eventually develop HCC [3], highlighting the importance of genetic susceptibility in HBV-related HCC. HBV genotypes have distinct geographic distributions, and the incidence of HCC varies in different regions of the world [4]. Because of small sample sizes, low success rates of HBV typing and different study designs, the previously reported effects of HBV genotypes on the outcomes of persistent HBV infections have varied greatly
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