title: Evidence of associations of APOBEC3B gene deletion with susceptibility to persistent HBV infection and hepatocellular carcinoma.
abstract: APOBEC3s are a family of cytidine deaminases involved in innate cellular immunity against virus including hepatitis B virus (HBV). A germline deletion across APOBEC3A and APOBEC3B (A3B) genes results in complete removal of the A3B coding region and destroys A3B expression. To determine whether this deletion affects susceptibility to HBV infection and HBV-related hepatocellular carcinoma (HCC), A3B genotypes were analyzed in 1124 individuals with HCC, 510 individuals with persistent HBV infection and 826 healthy controls and the association was estimated by odds ratio (OR) and 95% confidence interval (CI) computed by logistic regression. We also examined the effects of A3B on HBV genome hypermutation and replication in HCC cells. We observed a significantly higher frequency of the A3B deletion allele in persistent HBV carriers (33.3%; P = 0.0015) and HCC patients (37.9%; P = 1.28 × 10(-11)) compared with that in controls (27.5%). An increased risk for persistent HBV infection (OR = 1.35, 95% CI: 1.03-1.77) and HCC development (OR = 1.90, 95% CI: 1.58-2.28) was associated with at least one A3B deletion allele (+/- or -/- genotype) compared with the +/+ genotype. Transfection of A3B in HepG2 cells caused a substantial reduction of HBV RNA levels and G → A hypermutation in the HBV genome. Interestingly, a cytidine deaminase null mutant of A3B (E255A) also inhibited HBV RNA production although it was unable to edit HBV. These results suggest that the deletion of A3B attenuates HBV clearance, which in turn may result in persistent HBV infection and increased risk for developing HCC. Further studies are needed to verify our findings.
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Tongwen
authors.initials: T
authors.lastname: Zhang
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Cai
authors.forename: Jiang
authors.initials: J
authors.lastname: Chang
authors.forename: Dianke
authors.initials: D
authors.lastname: Yu
authors.forename: Chen
authors.initials: C
authors.lastname: Wu
authors.forename: Tao
authors.initials: T
authors.lastname: Yan
authors.forename: Kan
authors.initials: K
authors.lastname: Zhai
authors.forename: Xinyu
authors.initials: X
authors.lastname: Bi
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.forename: Wen
authors.initials: W
authors.lastname: Tan
authors.forename: Chunfeng
authors.initials: C
authors.lastname: Qu
authors.forename: Dongxin
authors.initials: D
authors.lastname: Lin
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics; D016022:Case-Control Studies; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism; D004198:Disease Susceptibility; D005260:Female; D017353:Gene Deletion; D006509:Hepatitis B / Q000201:enzymology* / Q000235:genetics / Q000821:virology; D006515:Hepatitis B virus / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011506:Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D011506:Proteins; C121399:APOBEC3A protein, human; D003564:Cytidine Deaminase