Research Papers:

Hepatitis B virus genotypes, expression quantitative trait loci for ZNRD1-AS1 and their interactions in hepatocellular carcinoma

Zhenzhen Liu, Ci Song, Juan Wen, Lu Xu, Yao Liu, Jian Zhu, Liguo Zhu, Zhibin Hu, Hongxia Ma _ and Li Liu

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Oncotarget. 2016; 7:44076-44083. https://doi.org/10.18632/oncotarget.9854

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Zhenzhen Liu1,*, Ci Song2,3,*, Juan Wen4, Lu Xu2, Yao Liu5, Jian Zhu6, Liguo Zhu7, Zhibin Hu2,3, Hongxia Ma2,3, Li Liu1

1Digestive Endoscopy Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

2Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China

3Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center of Cancer Medicine, Nanjing Medical University, Nanjing, China

4Nanjing Maternity and Child Health Care Institute, Nanjing Maternity and Child Health Care Hospital Affiliated with Nanjing Medical University, Nanjing, China

5Pathology Center and Department of Pathology, Soochow University, Suzhou, China

6Qidong Liver Cancer Institute, The First People’s Hospital of Qidong, Qidong, China

7Department of Infection Diseases, Jiangsu Province Center for Disease Prevention and Control, Nanjing, China

*These authors have contributed equally to this work

Correspondence to:

Hongxia Ma, email: hongxiama@njmu.edu.cn

Li Liu, email: kit9178@sina.com

Keywords: HCC, susceptibility, eQTL, HBV genotype, interaction

Received: March 08, 2016     Accepted: May 01, 2016     Published: June 6, 2016


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.

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