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Tumor Necrosis Factor-Alpha Gene Polymorphism Associated With Development of Hepatitis B Virus–associated Hepatocellular Carcinoma

Jin, Young-Joo, MD, PhD*; Lee, Danbi, MD, PhD; Chung, Young-Hwa, MD, PhD; Kim, Jeong A., MS; Kim, Sung Eun, MD, PhD§; Lee, Yoon-Seon, MD, PhD; Shin, Eun-Soon, PhD; Ryu, Soo Hyung, MD, PhD; Jang, Myoung Kuk, MD, PhD; Lee, Jong-Eun, PhD; Park, Neung Hwa, MD, PhD#

Journal of Clinical Gastroenterology: September 2015 - Volume 49 - Issue 8 - p e76–e81
doi: 10.1097/MCG.0000000000000261
ONLINE ARTICLES: Original Articles

Goal and Background: Host genetic diversity may play roles in development of HCC. This study was conducted to validate the effects of tumor necrosis factor-alpha (TNF-α) gene polymorphism on development of hepatocellular carcinoma (HCC) in patients chronically infected with hepatitis B virus (HBV).

Study: The study cohort comprised 224 patients with HBV-associated HCC and 206 with HBV-associated liver cirrhosis (LC). Using chromosomal DNA, TNF-α promoter gene polymorphisms were determined at 3 common single-nucleotide polymorphism (SNP) sites (TNF-α-1031 T>C, TNF-α-857 C>T, and TNF-α-308 G>A) using a single base extension method. The genotype distributions were compared between the 2 groups. All the HBV-associated LC patients were followed up regularly every 6 to 12 months for surveillance of HCC development.

Results: In the cross-sectional analysis, the frequency of TNF-α-857 T allele was much higher in patients with HCC compared with those with LC (42% vs. 31%, P<0.01). Of 206 HBV-associated LC patients, 12 (5.8%) developed HCC during the median follow-up period of 36 months. The cumulative occurrence rates of HCC were significantly higher in patients with TNF-α-857 T allele than those withTNF-α-857 C/C genotype (1-, 3-, and 5-y rates: 2.9%, 12.8%, and 20.7% vs. 0%, 3.1%, and 5.3%, respectively; P=0.013). However, the other genetic polymorphisms of TNF-α promoter gene did not affect the development of HCC. In multivariate analysis, TNF-α-857 T allele was a significant predictor of HCC development (hazard ratio 6.29, P=0.01).

Conclusion: Our data suggest that TNF-α-857 T allele is closely associated with development of HCC in HBV-associated LC patients.

*Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon

Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center

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Department of Internal Medicine, University of Inje College of Medicine, Seoul Paik Hospital

Department of Internal Medicine, Hallym University College of Medicine, Kangdong Sacred Heart Hospital, Seoul

§Department of Internal Medicine, Hallym University College of Medicine, Pyeongchon Sacred Heart Hospital, Pyeongchon

#Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Korea

Y.-J.J. and D.L. contributed equally.

A part of this work was presented at the 63rd annual meeting of the American Association for the Study of the Liver Diseases (AASLD) in 2012 (The Liver Meeting 2012).

Supported by a grant from Asan Institute for Life Science, Asan Medical Center, Republic of Korea (No. AILS10-498).

The authors declare that they have nothing to disclose.

Reprints: Young-Hwa Chung, MD, PhD, Department of Gastroenterology and Hepatology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro-43-gil, Songpa-gu, Seoul 138-736, South Korea (e-mail:

Received March 5, 2014

Accepted September 11, 2014

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