title: Expression quantitative trait loci in long non-coding RNA ZNRD1-AS1 influence both HBV infection and hepatocellular carcinoma development.
abstract: Zinc ribbon domain containing 1 (ZNRD1), cloned from human leukocyte antigen (HLA) region, may play integral roles in diverse processes including immune response against HBV infection and hepatocarcinogenesis. ZNRD1-AS1 (ZNRD1 antisense RNA 1) may be an important regulator of ZNRD1. By bioinformatics analyses, we identified that several single nucleotide polymorphisms (SNPs) in ZNRD1-AS1 may be expression quantitative trait loci (eQTLs) for ZNRD1. In this study, we hypothesized that these eQTLs SNPs in ZNRD1-AS1 may influence both chronic HBV infection and hepatocellular carcinoma (HCC) development. We designed a case-control study of 1300 HBV-positive HCC patients, 1344 HBV persistent carriers and, 1344 HBV natural clearance subjects to test the associations of three ZNRD1 eQTLs SNPs (rs3757328, rs6940552 and, rs9261204) in ZNRD1-AS1 with the risk of both chronic HBV infection and HCC. Logistic regression analyses in additive genetic model showed that variant alleles of all the three SNPs increased host HCC risk, whereas variant allele of rs3757328 was associated with HBV clearance. Moreover, the haplotype containing variant alleles of the three SNPs was significantly associated with both HCC development (adjusted OR = 1.18, 95% CI = 1.01-1.38, P = 0.035) and HBV clearance (adjusted OR = 0.83, 95% CI = 0.71-0.96, P = 0.013), when compared with the most frequent haplotype. In vitro experiments showed that ZNRD1 knockdown inhibited the expression of HBV mRNA and promoted proliferation of HepG2.2.15 cells. These findings suggest that ZNRD1 regulatory SNPs may be susceptibility makers for risk of both chronic HBV infection and HCC.
authors.affiliation: Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wen
authors.affiliation: Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary Surgery, Nantong Tumor Hospital, Nantong, China.
authors.forename: Jibin
authors.initials: J
authors.lastname: Liu
authors.affiliation: Digestive Endoscopy Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Ci
authors.initials: C
authors.lastname: Song
authors.affiliation: Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Infection Diseases, Jiangsu Province Center for Disease Prevention and Control, Nanjing, China.
authors.forename: Liguo
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Qidong Liver Cancer Institute, Qidong, China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Infection Diseases, Jiangsu Province Center for Disease Prevention and Control, Nanjing, China.
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Zhai
authors.affiliation: Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Hu
mesh_terms: D000483:Alleles; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000472:pathogenicity; D019694:Hepatitis B, Chronic / Q000235:genetics* / Q000821:virology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D016372:RNA, Antisense / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C406241:POLR1H protein, human; D016372:RNA, Antisense; D062085:RNA, Long Noncoding; D012333:RNA, Messenger
keywords: HCC; ZNRD1; eQTLs; susceptibility