Association of cytokine and DNA repair gene polymorphisms with hepatitis B-related hepatocellular carcinoma

Chun Chieh Chen, Shi Yi Yang, Chun Jen Liu, Chih Lin Lin, Yun Fan Liaw, Shi Ming Lin, Shou Dong Lee, Pei Jer Chen, Chien Jen Chen, Ming Whei Yu*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

98 Scopus citations


Background: Hepatitis B virus (HBV) induces hepatocellular carcinoma (HCC) mainly by causing chronic necroinflammatory hepatic disease. We investigated the mechanisms underlying the inflammatory hepatocarcinogenesis by examining whether genetic variations in cytokines, antioxidant enzymes, and DNA repair genes affect the HCC risk. Methods: We analyzed 10 polymorphisms in the genes for interleukin- 1β (IL-1B), interleukin-1-receptor antagonist (IL-1RN), tumor necrosis factor-α (TNF-A), glutathione S-transferase, XRCC1, hMLH1, and XPD in 577 HBV carriers with HCC and 389 HBV carrier controls. Results: Overall, only the hMLH1-93*A allele significantly increased HCC risk. We identified polymorphism combinations associated with HCC. In the presence of the IL-1RN*2 allele, adjusted odds ratios (ORs) for HCC associated with C/C, T/C, and T/T genotypes of the IL-1B-31 polymorphism were 1.00, 2.93 [95% confidence interval (95% CI) 1.07-8.07], and 5.76 (95% CI 1.79-18.53), respectively. There was a dose-dependent association between the number of putative high-risk genotypes in the IL-1B, TNF-A, hMLH1, and XRCC1 genes and HCC. The adjusted OR for HBV carriers with ≥3 putative high-risk genotypes was 9.29 (95% CI 2.90-29.75) compared with those with none or only one of the high-risk genotypes. These associations were not observed among HBV carriers without the IL-1RN*2 allele. Smoking modified the combined effect of multiple loci in the IL-1RN, IL-1B, TNF-A, hMLH1, and XRCC1 genes; a high-risk multilocus genotype only significantly increased the risk in smokers (adjusted OR 4.84; 95% CI 1.69-13.92). Conclusions: Genetic variations in cytokine and DNA repair genes contribute to susceptibility to HBV-related HCC. Smoking increased such genetic susceptibility.

Original languageEnglish
Pages (from-to)1310-1318
Number of pages9
JournalInternational Journal of Epidemiology
Issue number6
StatePublished - 12 2005


  • Cytokine
  • DNA repair
  • Hepatitis B
  • Hepatocellular carcinoma


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