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学科主题: 基础医学
题名:
Effect of functional nuclear factor-kappaB genetic polymorphisms on hepatitis B virus persistence and their interactions with viral mutations on the risk of hepatocellular carcinoma
作者: Zhang, Q.1; Ji, X. W.1; Hou, X. M.1; Lu, F. M.2; Du, Y.1; Yin, J. H.1; Sun, X. Y.1; Deng, Y.1; Zhao, J.3; Han, X.4; Yang, G. S.3; Zhang, H. W.1; Chen, X. M.2; Shen, H. B.5; Wang, H. Y.6; Cao, G. W.1
关键词: NF-kappa B ; polymorphism ; hepatitis B virus ; viral mutation ; hepatocellular carcinoma ; interaction
刊名: ANNALS OF ONCOLOGY
发表日期: 2014-12-01
DOI: 10.1093/annonc/mdu451
卷: 25, 期:12, 页:2413-2419
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Oncology
研究领域[WOS]: Oncology
关键词[WOS]: GENOTYPE C ; INCREASES ; HEPATOCARCINOGENESIS ; INFLAMMATION ; ASSOCIATION ; INFECTIONS ; CANCER ; LOAD
英文摘要:

Background: Nonresolving inflammation and viral mutations are important in hepatitis B virus (HBV)-induced hepatocarcinogenesis. However, the effects of genetic polymorphisms affecting nuclear factor-kappaB (NF-kappa B) on HBV persistence and generation of hepatocellular carcinoma (HCC)-related HBV mutations remain unknown.

Patients and methods: rs28362491 (NFKB1 -94Ins > Del), rs2233406 (NFKBIA -826C > T), rs3138053 (NFKBIA -881A > G), and rs696 (NFKBIA +2758G > A) were genotyped in 1342 healthy controls, 327 HBV-clearance subjects, and 3976 HBV-positive subjects including 1495 HCC patients, using quantitative PCR. HBV mutations were determined by sequencing. The NFKBIA promoter activity was assessed by transient transfection. Multiplicative interactions of the polymorphisms and viral mutations were assessed by multivariate logistic regression.

Results: Compared with HBV-clearance subjects, rs2233406 (CT versus CC) and rs3138053 (AG or AG + GG versus AA) significantly decreased HBV persistence, especially in the genotype B HBV-infected subjects. In the genotype C HBV-infected subjects, rs2233406 variant genotypes were significantly associated with an increased risk of HCC [CT versus CC: age-, gender-adjusted odds ratio (AOR), 1.33; 95% confidence interval (CI) 1.01-1.75 in training set and AOR, 1.59; 95% CI 1.01-2.52 in validation set] compared with HCC-free HBV-infected subjects and significantly increased the frequencies of HCC-related HBV mutations (A1762T/G1764A, T1753V, preS1 start codon mutation, and preS deletion); rs28362491 (Del/Del or Ins/Del + Del/Del versus Ins/Ins) significantly increased the frequency of A1762T/G1764A and reduced the frequency of preS2 start codon mutation. The variant genotypes impaired NFKBIA promoter activity in hepatic cells. The interaction of rs2233406 variant genotypes (CT + TT versus CC) with A1762T/G1764A significantly increased HCC risk in genotype C HBV-infected subjects, with AOR of 2.61 (95% CI 1.09-6.26).

Conclusion: Genetic polymorphisms improving NF-kappa B activity contribute to genotype B HBV clearance. The rs2233406 variant genotypes significantly increase HCC risk, possibly via facilitating immune selection of the HBV mutations. The host-virus interactions are important in identifying HBV-infected subjects who are more likely to develop HCC.

语种: 英语
所属项目编号: 81025015 ; 91129301 ; 81221061 ; 2015CB554006 ; 2012ZX10002-008 ; 12ZR1453600 ; 12ZR1429300 ; 20114066
项目资助者: National Natural Science Foundation of China ; National Key Basic Research Program (973 program) ; Key Project for Infectious Diseases of the Ministry of Science and Technology in China ; Science and Technology Commission of Shanghai Municipality ; Shanghai Health Bureau Fund
WOS记录号: WOS:000345825800016
Citation statistics:
内容类型: 期刊论文
版本: 出版稿
URI标识: http://ir.bjmu.edu.cn/handle/400002259/64299
Appears in Collections:基础医学院_病原生物学系_期刊论文

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作者单位: 1.Second Mil Med Univ, Dept Epidemiol, Shanghai 200433, Peoples R China
2.Peking Univ, Sch Basic Med Sci, Hlth Sci Ctr, Dept Microbiol, Beijing 100871, Peoples R China
3.Second Mil Med Univ, Eastern Hepatobiliary Surg Inst Hosp, Dept Hepatobiliary Surg, Shanghai 200433, Peoples R China
4.Ctr Dis Control & Prevent Yangpu Dist, Div Chron Dis, Shanghai, Peoples R China
5.Nanjing Med Univ, Dept Epidemiol & Biostat, Sch Publ Hlth, Nanjing, Jiangsu, Peoples R China
6.Second Mil Med Univ, Int Cooperat Lab Signal Transduct, Eastern Hepatobiliary Surg Inst Hosp, Shanghai 200433, Peoples R China

Recommended Citation:
Zhang, Q.,Ji, X. W.,Hou, X. M.,et al. Effect of functional nuclear factor-kappaB genetic polymorphisms on hepatitis B virus persistence and their interactions with viral mutations on the risk of hepatocellular carcinoma[J]. ANNALS OF ONCOLOGY,2014,25(12):2413-2419.
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