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Carcinogenesis Advance Access originally published online on October 1, 2009
Carcinogenesis 2009 30(11):1916-1922; doi:10.1093/carcin/bgp226
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© The Author 2009. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

IkappaBalpha gene promoter polymorphisms are associated with hepatocarcinogenesis in patients infected with hepatitis B virus genotype C

Yongchao He, Hongwei Zhang, Jianhua Yin, Jiaxin Xie, Xiaojie Tan, Shijian Liu, Qian Zhang1, Chengzhong Li1, Jun Zhao2, Hongyang Wang3 and Guangwen Cao*

Department of Epidemiology
1 Department of Infectious Diseases, the 1st Affiliated Hospital
2 Department of Hepatobiliary Surgery
3 Laboratory for Signal Transduction, the 3rd Affiliated Hospital, Second Military Medical University, Shanghai 200433, People's Republic of China

* To whom correspondence should be addressed. Tel/Fax: +86 818 71060; Email: gcao{at}smmu.edu.cn

Genetic predisposition of nuclear factor-kappa B (NF-{kappa}B)-signaling pathways linking inflammation to hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC) remains unresolved. We conducted a case–control study to determine the associations of the polymorphisms within the promoter regions of NFKB1 encoding NF-{kappa}B1 and NFKBIA encoding IkappaBalpha with the development of HCC. A total of 404 healthy controls, 482 non-HCC subjects with HBV infection and 202 patients with HCC were included. NFKB1 –94ATTG2 allele and GG allele in the 3'-untranslated region of NFKBIA were more prevalent in HCC patients than in the healthy controls. NFKBIA –826CT and NFKBIA –881AG allelic carriages were more prevalent in HCC patients than in the non-HCC subjects with HBV infection. The estimated haplotype frequency of NFKBIA promoter –881G–826T–519C was significantly higher in the patients with HCC than in the HBV-infected subjects without HCC (odds ratio = 3.142, P = 0.002). As compared with the HBV-infected subjects without HCC, NFKBIA –826 T and NFKBIA –881AG allelic carriages were only associated with HCC risk in the subjects with HBV genotype C. The association of NFKBIA –881AG allelic carriage with HCC risk was not affected by liver cirrhosis (LC) status, alanine aminotransferase level and hepatitis B e antigen status. By multivariate regression analysis, NFKB1 –94ATTG2, NFKBIA –826T, NFKBIA –881AG and HBV genotype C were independently associated with an increased risk of HCC. In conclusion, NFKB1 –94ATTG2 allele and haplotype –881G–826T–519C in NFKBIA promoter were associated with hepatocarcinogenesis. NFKBIA –826T and –881AG were associated with the risk of HCC in the subjects infected with HBV genotype C.

Abbreviations: ALT, alanine aminotransferase; AOR, adjusted odds ratios; ASC, asymptomatic hepatitis B surface antigen carriers; CHB, chronic hepatitis B; CI, confidence intervals; HBeAg, hepatitis B e antigen; HBV, Hepatitis B virus; HCC, hepatocellular carcinoma; I{kappa}B{alpha}, IkappaBalpha; LC, liver cirrhosis; NF-{kappa}B, nuclear factor-kappa B; PCR, polymerase chain reaction; SNP, single-nucleotide polymorphism; 3'-UTR, 3'-untranslated region; WT, wild type

Received July 6, 2009; revised August 14, 2009; accepted September 8, 2009.


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