title: Associations of pri-miR-34b/c and pre-miR-196a2 polymorphisms and their multiplicative interactions with hepatitis B virus mutations with hepatocellular carcinoma risk.
abstract: BACKGROUND
  Genetic polymorphisms of pri-miR-34b/c and pre-miR-196a2 have been reported to be associated with the susceptibility to cancers. However, the effect of these polymorphisms and their interactions with hepatitis B virus (HBV) mutations on the development of hepatocellular carcinoma (HCC) remains largely unknown. We hypothesized that these polymorphisms might interact with the HBV mutations and play a role in hepatocarcinogenesis.
  
  
  METHODS
  Pri-miR-34b/c rs4938723 (T>C) and pre-miR-196a2 rs11614913 (T>C) were genotyped in 3,325 subjects including 1,021 HBV-HCC patients using quantitative PCR. HBV mutations were determined by direct sequencing. Contributions of the polymorphisms and their multiplicative interactions with gender or HCC-related HBV mutations to HCC risk were assessed using multivariate regression analyses.
  
  
  RESULTS
  rs4938723 CC genotype was significantly associated with HCC risk compared to HBV natural clearance subjects, adjusted for age and gender (adjusted odds ratio [AOR] = 2.01, 95% confidence interval [CI] = 1.16-3.49). rs4938723 variant genotypes in dominant model significantly increased HCC risk in women, compared to female healthy controls (AOR = 1.85, 95% CI = 1.20-2.84) or female HCC-free subjects (AOR = 1.62, 95% CI = 1.14-2.31). rs4938723 CC genotype and rs11614913 TC genotype were significantly associated with increased frequencies of the HCC-related HBV mutations T1674C/G and G1896A, respectively. rs11614913 was not significantly associated with HCC risk, but its CC genotype significantly enhanced the effect of rs4938723 in women. In multivariate regression analyses, rs4938723 in dominant model increased HCC risk (AOR = 1.62, 95% CI = 1.05-2.49), whereas its multiplicative interaction with C1730G, a HBV mutation inversely associated with HCC risk, reduced HCC risk (AOR = 0.34, 95% CI = 0.15-0.81); rs11614913 strengthened the G1896A effect but attenuated the A3120G/T effect on HCC risk.
  
  
  CONCLUSIONS
  rs4938723 might be a genetic risk factor of HCC but its effect on HCC is significantly affected by the HBV mutations. rs11614913 might not be a HCC susceptible factor but it might affect the effects of the HBV mutations or rs4938723 on HCC risk.
authors.affiliation: Department of Epidemiology, Second Military Medical University, Shanghai, China.
authors.forename: Yifang
authors.initials: Y
authors.lastname: Han
authors.forename: Rui
authors.initials: R
authors.lastname: Pu
authors.forename: Xue
authors.initials: X
authors.lastname: Han
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Zhang
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yin
authors.forename: Jiaxin
authors.initials: J
authors.lastname: Xie
authors.forename: Qiuxia
authors.initials: Q
authors.lastname: Shen
authors.forename: Yang
authors.initials: Y
authors.lastname: Deng
authors.forename: Yibo
authors.initials: Y
authors.lastname: Ding
authors.forename: Weiping
authors.initials: W
authors.lastname: Li
authors.forename: Juhong
authors.initials: J
authors.lastname: Li
authors.forename: Hongwei
authors.initials: H
authors.lastname: Zhang
authors.forename: Guangwen
authors.initials: G
authors.lastname: Cao
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000821:virology; D004843:Epistasis, Genetic / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006515:Hepatitis B virus / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000821:virology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D012322:RNA Precursors / Q000235:genetics*; D012727:Sex Characteristics
chemical_list: C542543:MIRN196 microRNA, human; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D012322:RNA Precursors