Association of cytokine and DNA repair gene polymorphisms with hepatitis B-related hepatocellular carcinoma.
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-1beta (IL-1B), interleukin-1-receptor antagonist (IL-1RN), tumor necrosis factor-alpha (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 > or = 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.
Chen
Chun-Chieh
CC
Department of Family Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.
Yang
Shi-Yi
SY
Liu
Chun-Jen
CJ
Lin
Chih-Lin
CL
Liaw
Yun-Fan
YF
Lin
Shi-Ming
SM
Lee
Shou-Dong
SD
Chen
Pei-Jer
PJ
Chen
Chien-Jen
CJ
Yu
Ming-Whei
MW
D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000821:virology*; D002353:Carrier State; D016022:Case-Control Studies; D016207:Cytokines / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D019694:Hepatitis B, Chronic / Q000150:complications*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000821:virology*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012907:Smoking / Q000009:adverse effects
D016207:Cytokines