IJE Advance Access originally published online on September 19, 2005
International Journal of Epidemiology 2005 34(6):1310-1318; doi:10.1093/ije/dyi191
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Association of cytokine and DNA repair gene polymorphisms with hepatitis B-related hepatocellular carcinoma
1 Department of Family Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.
2 Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan.
3 Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
4 Department of Internal Medicine, Division of Gastroenterology, Taipei Municipal Jen-Ai Hospital, Taipei, Taiwan.
5 Liver Research Unit, Chang-Gung Memorial Hospital and Chang-Gung University College of Medicine, Taoyuan, Taiwan.
6 Department of Medicine, Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan.
* Corresponding author. Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, No. 1 Jen-Ai Road, Section 1, Rm 1550, Taipei 100, Taiwan. E-mail: mingwhei{at}ha.mc.ntu.edu.tw
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-1ß (IL-1B), interleukin-1-receptor antagonist (IL-1RN), tumor necrosis factor-
(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.
Keywords Cytokine, DNA repair, hepatitis B, hepatocellular carcinoma
Accepted 22 August 2005
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