Chen C.-C.Yang S.-Y.CHUN-JEN LIULin C.-L.Liaw Y.-F.Lin S.-M.Lee S.-D.PEI-JER CHENChen C.-J.MING-WHEI YU2021-07-032021-07-0320050300-5771https://www.scopus.com/inward/record.uri?eid=2-s2.0-84984545985&doi=10.1093%2fije%2fdyi191&partnerID=40&md5=a05f30c7a54d378e97993f244d1f7bb8https://scholars.lib.ntu.edu.tw/handle/123456789/568704Background: 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. ? The Author 2005; all rights reserved.[SDGs]SDG3antioxidant; cytokine; glutathione transferase; interleukin 1 receptor blocking agent; interleukin 1beta; tumor necrosis factor alpha; health and disease; adult; allele; article; cancer risk; confidence interval; controlled study; disease carrier; DNA repair; female; gene locus; genetic association; genetic polymorphism; genetic susceptibility; genetic variability; genotype; hepatitis B; high risk population; human; liver carcinogenesis; liver cell carcinoma; major clinical study; male; priority journal; smoking; Hepatitis B virusjournal article10.1093/ije/dyi191161721012-s2.0-84984545985