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Associations of pri-miR-34b/c and pre-miR-196a2 Polymorphisms and Their Multiplicative Interactions with Hepatitis B Virus Mutations with Hepatocellular Carcinoma Risk

Author

Listed:
  • Yifang Han
  • Rui Pu
  • Xue Han
  • Jun Zhao
  • Yuwei Zhang
  • Qi Zhang
  • Jianhua Yin
  • Jiaxin Xie
  • Qiuxia Shen
  • Yang Deng
  • Yibo Ding
  • Weiping Li
  • Juhong Li
  • Hongwei Zhang
  • Guangwen Cao

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.

Suggested Citation

  • Yifang Han & Rui Pu & Xue Han & Jun Zhao & Yuwei Zhang & Qi Zhang & Jianhua Yin & Jiaxin Xie & Qiuxia Shen & Yang Deng & Yibo Ding & Weiping Li & Juhong Li & Hongwei Zhang & Guangwen Cao, 2013. "Associations of pri-miR-34b/c and pre-miR-196a2 Polymorphisms and Their Multiplicative Interactions with Hepatitis B Virus Mutations with Hepatocellular Carcinoma Risk," PLOS ONE, Public Library of Science, vol. 8(3), pages 1-9, March.
    • Handle: RePEc:plo:pone00:0058564
    DOI: 10.1371/journal.pone.0058564
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    1. Eran Hornstein & Jennifer H. Mansfield & Soraya Yekta & Jimmy Kuang-Hsien Hu & Brian D. Harfe & Michael T. McManus & Scott Baskerville & David P. Bartel & Clifford J. Tabin, 2005. "The microRNA miR-196 acts upstream of Hoxb8 and Shh in limb development," Nature, Nature, vol. 438(7068), pages 671-674, December.
    2. Shengping Li & Ji Qian & Yuan Yang & Wanting Zhao & Juncheng Dai & Jin-Xin Bei & Jia Nee Foo & Paul J McLaren & Zhiqiang Li & Jingmin Yang & Feng Shen & Li Liu & Jiamei Yang & Shuhong Li & Shandong Pa, 2012. "GWAS Identifies Novel Susceptibility Loci on 6p21.32 and 21q21.3 for Hepatocellular Carcinoma in Chronic Hepatitis B Virus Carriers," PLOS Genetics, Public Library of Science, vol. 8(7), pages 1-8, July.
    3. Jing Guo & Mingjuan Jin & Mingwu Zhang & Kun Chen, 2012. "A Genetic Variant in miR-196a2 Increased Digestive System Cancer Risks: A Meta-Analysis of 15 Case-Control Studies," PLOS ONE, Public Library of Science, vol. 7(1), pages 1-7, January.
    4. Zhongxia Wang & Yin Cao & Chunping Jiang & Guang Yang & Junhua Wu & Yitao Ding, 2012. "Lack of Association of Two Common Polymorphisms rs2910164 and rs11614913 with Susceptibility to Hepatocellular Carcinoma: A Meta-Analysis," PLOS ONE, Public Library of Science, vol. 7(6), pages 1-8, June.
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    1. Tie-Jun Liang & Hong-Jun Liu & Xiao-Qian Zhao & Cui-Hua Yu & Chen-Sheng Li, 2013. "Lack of Association of MiR-34b/c Polymorphism (rs4938723) with Hepatocellular Carcinoma: A Meta-Analysis," PLOS ONE, Public Library of Science, vol. 8(7), pages 1-5, July.

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