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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Article |
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
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Abstract |
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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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Introduction |
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There are more than 350 million chronic carriers of hepatitis B virus (HBV) worldwide.1 In most studies, the relative risk for developing hepatocellular carcinoma (HCC) is
20 among chronic HBV carriers compared with the non-carriers.2 It has been noted that the risk of HCC for HBV carriers increases with the severity of hepatic inflammation.3 However, the molecular basis of the inflammatory hepatocarcinogenesis caused by HBV remains largely unsolved. Cytokines modulate inflammation.4–10 The presence of inflammatory cells along with the production of inflammatory cytokines activates cellular oxidant-generating pathways.10,11 Reactive oxygen species that are generated in inflammatory conditions induce oxidative DNA damage.10–14 Antioxidant enzymes, such as glutathione S-transferases (GSTs) that are up-regulated in oxidative stress, play an important role in cellular protection by conjugating oxygen-derived free radicals with reduced glutathione.15,16
Genetic polymorphisms affecting the function of cytokines or other factors that are involved in the accumulation/removal of reactive oxygen species or repair of oxidative DNA lesions are potentially good candidates as factors that influence susceptibility to HBV-related HCC. We have previously demonstrated17 that a functional polymorphism in the XRCC1 gene, which participates in the base-excision repair of oxidative DNA damage,18,19 was associated with increased risk of early-onset HCC among HBV carriers. Moreover, various combinations of GSTM1 and GSTT1 genotypes modified the association between XRCC1 and HCC.17 We expanded this study to incorporate cytokine and other DNA repair gene polymorphisms. We analysed five polymorphisms located in three cytokine genes—interleukin-1ß (IL-1B), interleukin-1-receptor antagonist (IL-1RN), and tumor necrosis factor- (TNF-A). IL-1ß and TNF- are strong inducers of inflammation, while IL-1-receptor antagonist is an anti-inflammatory molecule that competes for receptor binding with IL-1ß.8–10,20 We also selected polymorphisms in the hMLH1 and XPD genes, which participate in the DNA mismatch repair and nucleotide excision repair, respectively.18,21 This study was based on the candidate gene approach. Genetic polymorphisms selected for the study have been correlated with gene function, inflammation conditions, and/or cancer risk.4–7,15–17,22–31 By using the data from our case–control study of 966 HBV carriers we assessed the independent and interactive effects of these polymorphisms on the risk for HCC.
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Materials and methods |
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Patients and controls
The sources and characteristics of the study subjects have been described previously.17 Case patients were recruited constitutively from three major hospitals (Chang-Gung Memorial Hospital, Taipei Veterans General Hospital, and National Taiwan University Hospital) in northern Taiwan between September 1, 1997 and December 31, 2001. A total of 577 hepatitis B surface antigen (HBsAg) carriers with incident HCC diagnosed by liver biopsy or the combination of increased
-fetoprotein (400 ng/ml) and typical features on angiography, sonography, or computed tomography were studied. The control group comprised 389 HBsAg carriers without HCC who were frequency-matched to the case patients by sex and year of birth within 10-year categories. Control subjects were selected from a cohort of HBsAg carriers by the method of stratified random sampling.17 All the HBV carrier controls are being followed up through various channels, including a clinical evaluation with ultrasonography measurement and conventional liver function tests every 6–12 months and a data linkage with Taiwan's national cancer registry and death certification systems. Controls were unrelated to any of the cases in this study.
The interview for all the study subjects included questions on cigarette smoking, alcohol consumption, family history, and demographic information. The study protocol was approved by the research ethics committee at the College of Public Health, National Taiwan University and by the appropriate institutional review board. All the study participants provided written informed consent.
Genotyping
DNA was extracted from frozen white blood cells using standard methods. The GSTM1 and GSTT1 genotypes and the arginine-to-glutamine polymorphism at codon 399 in the XRCC1 gene (XRCC1-Arg399Gln polymorphism) were determined as previously described.17 For seven additional polymorphisms examined in this study, PCR-based assays were used to determine the genotypes. The PCR primer/probe sequences are listed in Table 1. In the analysis of the 86 bp variable number of tandem repeat (VNTR) polymorphism in intron 2 of IL-1RN, the PCR conditions were as follows: a denaturing step at 94°C for 4 min, 35 cycles of 94°C for 30 s, 60°C for 30 s, 72°C for 1 min, and a final extension at 72°C for 10 min. After amplification, the amplicon was visualized on an ethidium bromide stained 2% agarose gel.
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The hMLH1-93, IL-1B-511, and IL-1B+3954 polymorphisms were genotyped using PCR-restriction fragment length polymorphism assays. The PCR reaction consisted of an initial denaturation at 94°C for 4 min followed by 35 cycles of 94°C for 40 s, 55°C for 30 s, 72°C for 40 s, and a final extension at 72°C for 10 min. The PCR product was digested with the restriction enzyme (hMLH1-93 with PvuII, IL-1B-511 with AvaI, and IL-1B+3954 with TaqI) obtained from New England Biolabs, Beverly, MA. The digestion products were electrophoresed on 2.5% agarose gels containing ethidium bromide (Figure 1).
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Genotyping of IL-1B-31, TNF-A-308, and the lysine-to-glutamine polymorphism at codon 751 in the XPD gene (XPD-Lys751Gln polymorphism) was performed using 5' nuclease PCR assays (TaqMan). PCR conditions were 50°C for 2 min, 95°C for 10 min, then 40 cycles of 95°C for 15 s and 60°C for 1 min. The ABI PRISM 7000 Sequence Detection System (Applied Biosystems) was used for data acquisition.
Statistical analysis
Hardy–Weinberg equilibrium of alleles at individual loci was assessed by using exact tests. Linkage disequilibrium coefficients D' = D/Dmax for pairs of alleles were calculated using the PowerMarker software program,32 and their statistical significance was examined by using the 
2-test. Categorical variables were compared with use of the 2 test or Fisher's exact test (when one expected value was <5). Unconditional logistic regression was undertaken to estimate odds ratios (ORs) and their 95% confidence intervals (95% CIs) after controlling for year of birth (continuous variable), sex, cigarette smoking (yes or no), alcohol consumption (yes or no), and first-degree family history of HCC. For single gene polymorphism associations, P-values were corrected for multiple comparisons (Pc) by multiplying by the number of markers tested. Linear trends of allele–dosage relationships were tested in logistic regression by using an ordered categorical variable. The likelihood ratio test was used to determine the statistical significance of interaction between gene polymorphisms with respect to risk for HCC. The test compares a main-effect in a no interaction model with a fully parameterized model containing all possible interaction terms for the variables of interest. All statistical tests were two-sided.
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Results |
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The mean age at enrollment in this case–control study (i.e. in 2002) was 52.3 ± 12.7 years (±standard deviation) for cases and 53.0 ± 12.5 years for controls. Cases and controls had identical sex distributions (14% were women).
Among controls, the alleles at all of the individual loci, except GSTM1 and GSTT1 (for which the status of homozygous gene deletion could not be differentiated from the heterozygous status), were in Hardy–Weinberg equilibrium. Overall, only the hMLH1-93*A allele frequency was significantly increased in patients with HCC than in controls (60.3% vs 53.5%; P = 0.0037; Pc = 0.037). The multivariate-adjusted ORs associated with HCC for G/G, G/A, and A/A genotypes of the hMLH1-93 polymorphism were 1.00, 1.53 (95% CI 1.05–2.22), and 1.85 (95% CI 1.24–2.75), respectively (Table 2).
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We further assessed the interaction of IL-1RN and IL-1B genotypes in HCC because studies have suggested a synergistic effect between the two genes in the production of IL-1ß and inflammation.5,6 We divided the IL-1RN genotypes into two groups according to the presence or absence of the IL-1RN*2 allele because the IL-1RN*2 allele has been associated with increased production of IL-1ß.5,23 Table 3 shows that the association between IL-1B-31 and HCC is modified by the IL-1RN genotype (P-value for interaction = 0.0068). In the presence of the IL-1RN allele 2 (IL-1RN*2), a dose-dependent association between increasing number of the IL-1B-31*T allele and HCC was observed (P-value for linear trend = 0.0036). Both T/C and T/T genotypes of the IL-1B-31 polymorphism were associated with increased risks for HCC [adjusted OR 2.93 (95% CI 1.07–8.07) and adjusted OR 5.76 (95% CI 1.79–18.53), respectively] compared with the C/C genotype. Conversely, among HBsAg carriers without the IL-1RN*2 allele, no increased risk associated with the IL-1B-31 genotype was seen. In controls, IL-1B-31 and IL-1B-511 loci were in near-complete inverse linkage disequilibrium (D' = 0.94, P = 0.000). Similar association with HCC was thus observed for the IL-1B-511*C allele.
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The IL-1RN gene is the only anti-inflammatory cytokine gene studied.9 Since altered balance of pro-inflammatory and anti-inflammatory cytokines induces excessive inflammation and then oxidative DNA damage,10 we also assessed the interaction between the IL-1RN*2 allele and other gene polymorphisms involved in inflammation or DNA repair. Although the interactions of the IL-1RN*2 allele with the IL-1B+3954, TNF-A-308, hMLH1-93, and XRCC1-Arg399Gln polymorphisms were not statistically significant, the associations between these polymorphisms and HCC appeared to be stronger for HBsAg carriers with the IL-1RN*2 allele (Table 3).
Table 4 presents the joint contribution of multiple loci to the increased risk of HCC. Subjects were classified according to the number of putative high-risk genotypes (including hMLH1-93 G/A+A/A, XRCC1 Arg/Gln+Gln/Gln, the compound genotype containing both the IL-1B-31*T and IL-1B-511*C alleles, IL-1B+3954 C/T+T/T, and TNF-A-308 A/A). Among HBsAg carriers harboring the IL-1RN*2 allele, the proportion of having two or more putative high-risk genotypes was found to be significantly increased in the cases compared with the controls (82.1% vs 54.2%; P = 0.001). We found that the risk of HCC increased with the increasing number of high-risk genotypes (P-value for linear trend = 0.0002). Adjusted ORs of HCC for HBsAg carriers with 
1, 2, and 3 putative high-risk genotypes were 1.00, 2.95 (95% CI 1.08–8.06), and 9.29 (95% CI 2.90–29.75), respectively. However, this association was not found among HBsAg carriers without the IL-1RN*2 allele.
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The risk of HCC associated with the high-risk multilocus genotype, defined as the genotype harbouring the IL-1RN*2 allele combined with
2 putative high-risk genotypes of the hMLH1, XRCC1, IL-1B, and TNF-A polymorphisms according to Table 4, was further examined by stratifying for sex, onset age, status of tobacco, and alcohol use, and first-degree family history of HCC (Table 5). The increased risk of HCC associated with the high-risk multilocus genotype was higher for smokers (adjusted OR 4.84; 95% CI 1.69–13.92) than for non-smokers (adjusted OR 1.30; 95% CI 0.70–2.41). The interaction between smoking and the high-risk multilocus genotype was statistically significant (P = 0.0189). Other stratified factors did not modify the effect of the high-risk multilocus genotype.
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Discussion |
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The risk of HCC among chronic HBV carriers is related closely to chronic hepatitis and liver cirrhosis,3 which in part are mediated by cytokines.9 Increased oxidative stress caused by chronic inflammation can produce genetic mutations and gross chromosomal alterations.10–12 Extensive oxidative DNA damage has been detected in hepatocytes of HBV-transgenic mice and humans with chronic hepatitis.13,14
Any gene associated with inflammation, accumulation of reactive oxygen species, or repair of oxidative DNA lesions is a potential candidate to modify individual susceptibility to HCC. XRCC1 participates in the repair of oxidatively induced DNA damages,18,19 and the Gln allele of the XRCC1-Arg399Gln polymorphism was associated with lower efficiency of DNA repair.26 Our previous study has suggested that the XRCC1-Arg399Gln polymorphism is associated with the development of HCC and the status of GSTM1 and GSTT1 genes might modify this association.17 Here we further report a battery of gene polymorphisms in cytokines and DNA repair pathways associated with increased risk for HCC.
IL-1ß is a potent pro-inflammatory cytokine in initiating and amplifying inflammatory response. IL-1-receptor antagonist competitively binds to IL-1ß receptors, thereby modulating the effect of IL-1ß.4–7,9,20 In this study, the less common allele 2 of the IL-1RN VNTR polymorphism alone did not increase the risk of HCC. However, we observed a strong and statistically significant modification of the IL-1B gene effect by the IL-1RN*2 allele. In the presence of the IL-1RN*2 allele, an 5-fold increased risk of HCC was found for HBsAg carriers harbouring the IL-1B-31 T/T or IL-1B-511 C/C genotype compared with those harbouring the IL-1B-31 C/C or IL-1B-511 T/T genotype. In contrast, among HBsAg carriers without the IL-1RN*2 allele, there was no evidence that the IL-1B-31 T/T or IL-1B-511 C/C genotype increased the disease risk.
The IL-1RN*2 allele alone has been associated with the increased production of IL-1ß.5,23 Studies also suggested that this allele and IL-1B genotypes synergistically interacted in the production of IL-1ß and inflammation.5,6 IL-1B-31 is a TATA-box polymorphism, which markedly affects DNA–protein (presumably transcription factors) interactions in vitro.22 IL-1B-511 is in strong linkage disequilibrium with IL-1B-31, but haplotype frequency distributions depend on ethnicity.4,5,22,25 The IL-1RN*2 and the IL-1B-31*T or IL-1B-511*T alleles have been found to confer an increased risk of gastric cancer for which Helicobacter pylori-induced gastritis is a major risk factor.6,7,22 The near-complete inverse linkage disequilibrium between IL-1B-31 and IL-1B-511 loci observed in our study population is similar to that reported in Japan.4,5,25 A Japanese case–control study has shown that the IL-1B-31 T/T genotype was associated with an increased risk for hepatitis C-related HCC, whereas the IL-1RN VNTR polymorphism was not a risk factor. However, that study included only 125 HCC patients and could not assess the interaction between polymorphisms of the IL-1RN and IL-1B genes due to the infrequency of the IL-1RN*2 allele among the Japanese.25
Reactive oxygen species released from inflammatory cells or induced by inflammatory cytokines are capable of producing a variety of different types of oxidative DNA lesions, including base modifications, frameshift mutations, and DNA strand break.11,12,33,34 XRCC1 is involved in the base excision repair pathway,18,19 while hMLH1 is related to the DNA mismatch repair system that plays a crucial role in the repair of frameshift mutations after oxidative stress.33,34 Loss of the hMLH1 function has been associated with the acquisition of a mutator phenotype and is a major aetiological factor for hereditary nonpolyposis colorectal cancer.21,35
In this study, a G/A polymorphism at nucleotide position –93 in the hMLH1 promoter region was an independent risk factor for HCC. Moreover, a strong synergistic interaction in HCC development was found between the IL-1RN*2 allele and the combined effect of multiple loci in pro-inflammatory cytokines and/or DNA repair pathways. In the presence of the IL-1RN*2 allele, HBsAg carriers harbouring 2 or more putative high-risk genotypes of the IL-1B, TNF-A, hMLH1, and XRCC1 polymorphisms had from 3-fold to 9-fold higher risk of HCC than those with only one or none of the high-risk genotypes. In the absence of the IL-1RN*2 allele, however, there was no such association. These results implicated that sustained inflammation due to an imbalance of anti-inflammatory and pro-inflammatory cytokines in the context of persistent HBV infection can be associated with increased oxidative DNA damage, and that impaired DNA repair capacity potentiate and/or promote the development of HCC.
We also found that smokers had a significantly higher HCC risk associated with the combined effect of the putative high-risk genotypes in anti-inflammatory/pro-inflammatory cytokine and DNA repair genes than those who never smoked (Table 5). Although smoking and alcohol consumption are generally related, this modification effect by smoking was not observed for alcohol consumption. Since tobacco smoke contains a number of chemicals that could deplete antioxidants or induce oxidative DNA base modifications,36 the synergistic interaction between smoking and the high-risk multilocus genotypes in anti-inflammatory/pro-inflammatory cytokines and DNA repair pathways, which participate in the generation/removal of oxidative DNA lesions, is biologically plausible.
There is also evidence that smoking may influence all aspects of the immune system,37 although its effect on immunity to HBV has not been stressed in previous investigations. Besides HCC, smoking has been associated with an increased risk for developing liver cirrhosis in HBsAg carriers under routine follow-up clinical evaluation,38 and a higher hepatitis activity manifested by elevated serum levels of alanine aminotransferase among individuals with hepatitis C virus infection.39 These results together with our findings suggest that abstinence from smoking by HBV carriers could probably reduce their hepatic necroinflammatory activity and prevent its progression into HCC.
In conclusion, this report indicates that genetic polymorphisms determining the function of inflammatory cytokines and the efficiency of repair of oxidative DNA damage contribute to the pathogenesis of HCC among HBsAg carriers. Smoking, which is an external source of oxidative DNA damage, may be able to induce diverse alterations in the immune system that can increase such genetic susceptibility to HBV-related HCC. In addition to smoking, there may be interactions between HBV viral factors and cytokine gene polymorphisms. HBV-related factors, such as viral genotype and DNA levels in blood, have been associated with the risk of HCC.40 Since HBV DNA levels might change after the onset of HCC, further studies using nested case–control study design are needed for a more in-depth analysis of the interaction between HBV viral factors and cytokine gene polymorphisms in the development of HCC.
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Acknowledgments |
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This study was supported by grants from the National Science Council (NSC 93-2320-B-002-049) and the National Research Program of Genomic Medicine, Department of Health, Executive Yuan (DOH92-TD-1054), Taiwan. The authors thank the Core Laboratory of Population Genetic Polymorphisms at the National Taiwan University Center in Genomic Medicine for technical support. Dr Chen CC is the receipt of an investigator award of the Liver Disease Prevention and Treatment Research Foundation.
KEY MESSAGES
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