Hepatitis B and C Viruses Infection, Lifestyle and Genetic Polymorphisms as Risk Factors for Hepatocellular Carcinoma in Haimen, China

A case‐control study was carried out to investigate the impact of factors including virus infection, aflatoxin B1, microcystins, smoking/drinking and dietary habits as well as genetic polymorphisms of aldehyde dehydrogenase 2 (ALDH2) and cytochrome P4502E1 (CYP2E1), on susceptibility to hepatocellular carcinoma (HCC) in Haimen, China. A total of 248 patients with HCC and 248 sex‐, age‐ and residence‐matched population‐based controls were recruited into the study. Virus infection, and ALDH2 and CYP2E1 gene polymorphisms were assessed in 134 paired cases and controls. By univariate analysis, hepatitis B virus (HBV) infection (odds ratio [OR]=9.75; 95% confidence interval [CI] =4.71–20.2), history of intravenous injection (OR=1.50; 95%CI=1.02–2.22), average income (OR=0.63; 95% CI=0.43–0.92), frequent intake of foods rich in protein, e.g., egg (OR=0.6; 95% CI=0.42–0.87), chicken (OR=0.53; 95% CI=0.35–0.79), pork (OR=0.67; 95% CI=0.46–0.98) and fresh fish (OR=0.58; 95% CI=0.39–0.87) significantly differed between cases and controls. However, peanut intake (OR=0.66; 95% CI=0.43–1.01), source of drinking water, including tap (OR=1.33; 95% CI=0.81–2.20), deep well (OR=0.94; 95% CI=0.56–1.55), shallow well (OR=0.85; 95% CI=0.55‐–1.30), river (OR=0.95; 95% CI=0.65–1.38), ditch (OR=1.09; 95% CI=0.76–1.55) and pond water (OR=1.0; 95% CI=0.14–7.10) were not significantly associated with risk. Univariate analysis also indicated that the 1–1 genotype of ALDH2 (OR=1.38; 95% CI=0.86–2.23) as well as the Pst1‐ and Rsa1‐digested c1/c1 genotype of CYP2E1 (OR=1.36; 95% CI=0.81–2.28), was slightly more frequent in the case group. On multivariate analysis, HBV infection (OR=13.9; 95% CI=5.78–33.6) and history of intravenous injection (OR=2.72; 95% CI=1.24–6.00) were still associated with significantly increased risk of HCC, while frequent intake of fresh fish (OR=0.32; 95% CI=0.12–0.86) decreased this risk. These findings suggest that whereas peanut intake, water sources as well as genetic polymorphisms in ALDH2 and CYP2E1 do not significantly correlate with the risk of HCC, HBV infection is a main risk factor, and dietary items rich in protein, especially fresh fish, might protect against the risk of HCC in Haimen, China.     

A Population-based Case-control Study of Risk Factors and Genetic Polymorphisms of ALDH2 and P4502E1 for Hepatocellular Carcinoma in Nagoya,Japan

A population-based case-control study was carried out to investigate risk factors for hepatocellular carcinoma ‍(HCC) in Nagoya, Japan, including hepatitis virus infections, drinking and smoking habits and genetic polymorphisms ‍in aldehyde dehydrogenase2 (ALDH2) and cytochrome P4502E1 (CYP2E1). A total of 84 patients with HCC and 84 ‍sex, age and residence pair-matched controls were recruited for this study. By univariate analysis, hepatitis B virus ‍(HBV) (OR=5.14; 95%CI=2.29-11.6) and hepatitis C virus (HCV)(OR=32.00; 95%CI=7.83-130.7) infections, having ‍a history of blood transfusion (OR=5.25; 95%CI=1.80-15.29), and habitual smoking (OR=2.36; 95%CI=1.17-4.78) ‍were significantly linked to cases; by multivariate analysis, HCV infection (OR=23.5; 95%CI=5.07-108.9) and habitual ‍smoking (OR=5.41; 95%CI=1.10-26.70) were still associated with a significantly increased risk. The c1/c1 genotype ‍of CYP2E1 (odds ratio [OR]= 0.45; 95% confidence interval [CI]=0.21-0.99), detected by Pstl and Rsal digestion was ‍significantly more prevalent in the control group, while 1-1 genotype of ALDH2 (OR=1.24; 95%CI=0.70-2.20) did ‍not demonstrate variation. There were no statistically significant interactions between habitual smoking/drinking ‍and genetic polymorphisms of ALDH2/P4502E1 with reference to HCC development. These findings suggest that ‍viruses, especially HCV infection, and habitual smoking are major independent risk factors, while genetic ‍polymorphisms of ALDH2 and CYP2E1 have only limited contribution to the risk of HCC in Nagoya, Japan.     

Alcohol dehydrogenase-2 and aldehyde dehydrogenase-2 genotypes, alcohol drinking and the risk of primary hepatocellular carcinoma in a chinese population.

Objective: To investigate the relationship of alcohol dehydrogenase-2 (ADH2) and aldehyde dehydrogenase-2 (ALDH2) genotypes as well as alcohol drinking to the susceptibility of primary hepatocellular carcinoma (HCC). Methods: A case-control study including 208 cases of HCC and 208 controls matched with sex, age and residential area was carried out in Taixing city of Jiangsu province, China. Blood samples were collected and tested for ADH2 and ALDH2 genotypes by PCR-RFLP method. Results: There were no significant differences in the frequency of either ADH2 or ALDH2 genotypes between cases and controls. Compared with no-drinkers possessing ALDH21*1 genotypes, drinkers with ALDH21*2 or ALDH22*2 genotypes and cumulative amount of alcohol consumption >3 (Kg * years) were at a significantly higher risk of developing HCC (OR=3.30, 95%CI: 1.24-8.83). In contrast, there was no significant difference in cancer risk between no-drinkers with ADH21*1 and drinkers with ADH2 1*2 or ADH22*2 genotypes. A dose-dependent positive result was found (P=0.044) between cumulative amount of alcohol consumption and the risk of HCC in individuals carrying ALDH21*2 or ALDH22*2 genotypes. Drinkers with cumulative amount of alcohol consumption >3 (Kg * years) who possessed both inactive ALDH2 (ALDH21*2 or ALDH22*2) and inactive ADH (ADH21*2 or ADH22*2) genotypes were not at a significantly higher risk of HCC (adjusted OR=4.26, 95%CI: 0.63-29.08) compared to no-drinkers possessing ADH21*1 and ALDH21*1 genotypes. Compared with individuals possessing ALDH21*1, with negative HBsAg and cumulative amount of alcohol consumption 3 (Kg * years) had a significantly higher risk of HCC (OR=49.71, 95%CI: 5.51-448.96). Conclusion: These results revealed that it was not ADH2 but ALDH2 polymorphisms that had a significant interaction with heavy alcohol consumption in the development of HCC. This result suggests that to help lower their risk for HCC , persons with ALDH21*2 or ALDH22*2 genotypes should be encouraged to reduce their consumption of alcoholic beverages.     

Synergistic Action of Clonorchiasis, HBV Infection and Alcohol Consumption on Primary Hepatocellular Carcinoma

OBJECTIVE It has been recognized that HBV infection and alcohol consumption are two important risk factors for primary hepatocellular carcinoma(HCC).Recently,the role of clonorchiasis as a risk factor for HCC is controversial.We aimed to investigate whether these factors increase the risk of HCC in Guangxi,China.METHODS A hospital-based,case-control study of HCC was conducted from July 2005 to July 2007.We enrolled 500consecutive patients with HCC as an experimental group and 500patients without tumor in liver as a control group.nle risk factors that the patients were exposed to were assessed.RESULTS Comparing the risks of developing the HCC,we found out the following results.The risk of developing HCC for the patients with clonorchiasis was 5 folds of that for the patients without clonorchiasis(OR=5.0;95%CI:3.1-8.1),and the risk for the patients with alcohol consumption was 3 folds of that for the patients without drinking alcohol(OR=3.4;95%CI:2.3-4.9),and similarly,the risk for the patients with HBV infection was 21 times of that for the patients without HBV infection (OR=20.6;95% CI:14.3-29.7).According to crossover analysis,there was significant interaction among clonorchiasis,HBV infection and alcohol consumption,with synergistic indices greater than 1.The etiologic fractions attributed to these interactions [EF(A x B)] are 0.7465,0.5789 and 0.5506,respectively.CoNCLUSION Clonorchiasis,HBV infection and heavy alcohol consumption are independent risk factors for developing HCC in our population in Guangxi,and as they can interact synergistically,the risk of developing HCC is increased.Data from this study may indicate new prevention strategies of developing HCC in hish-risk individuals.     

Influence of alcohol consumption and gene polymorphisms of ADH2 and ALDH2 on hepatocellular carcinoma in a Japanese population

Although alcohol intake as well as hepatitis viruses has been associated with hepatocellular carcinoma (HCC), gene-alcohol interactions on HCC risk remain to be elucidated. We conducted a case-control study to examine whether polymorphisms of alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) modified the HCC risk depending on the amount of alcohol intake. ADH2 and ALDH2 genotyping was performed by a duplex polymerase chain reaction with confronting two-pair primers in 209 newly diagnosed HCC cases and 2 different controls [275 hospital controls and 381 patients with chronic liver disease (CLD)]. Multiple logistic regression analyses revealed that heavy drinkers consuming >or=3 "go"s/day of sake (69 g of ethanol/day) showed an increased risk of HCC based on comparison of HCC cases with hospital controls [adjusted odds ratio (OR) = 13.5; 95% confidence interval (CI) 3.3-54.3] or CLD patients (adjusted OR = 7.0; 95% CI 2.5-19.2), whereas the overall risk was not elevated among light to moderate drinkers consuming <3 "go"s/day. Interestingly, light to moderate drinking was associated with an increased risk among those with ALDH2*1/*2 (adjusted OR = 4.5 or 2.0), but not among those with ALDH2*1/*1 (adjusted OR = 0.8 or 1.0; p interaction = 0.03 or 0.13). However, this gene-alcohol interaction was not observed for heavy drinking. Among light to moderate drinkers, people with the combination of ALDH2*1/*2 and ADH2*2/*2 revealed the highest risk of HCC. These findings indicate that the ALDH2 polymorphism may modify HCC risk among light to moderate drinkers.     

CYP2C19 Genotype Could be a Predictive Factor for Aggressive Manifestations of Hepatocellular Carcinoma Related with Chronic Hepatitis B Infection in Thailand

Background: Chronic hepatitis B virus (HBV) infection related hepatocellular carcinoma (HCC) is a majorhealth problem in the Asia-Pacific region including Thailand. Several factors have been proposed as contributingto hepatocarcinogenesis. This study was aimed to investigate the impact of CYP2C19 genotypic polymorphismin HCC related to chronic HBV infection in Thailand. Materials and Methods: A cross-sectional study wasperformed between April 2014 and January 2015. Chronic HBV patients with HCC (n=50) and without HCC(n=50) were included. Clinical information and blood samples of all patients were collected. The CYP2C19genotype was determined by polymerase chain reaction-restriction fragment length polymorphism method, andwas classified as rapid metabolizer (RM), intermediate metabolizer (IM) or poor metabolizer (PM). Results:The CYP2C19 genotype frequencies of RM, IM and PM in HBV patients were found to be 19/50 (38%), 25/50(50%) and 6/50 (12%), respectively. The CYP2C19 genotype frequencies of RM, IM and PM in HBV with HCCpatients were 21/50 (42%), 25/50 (50%) and 4/50 (8%), respectively. The distribution of CYP2C19 genotype wasnot different between patients with and without HCC. Interestingly, among HBV with HCC patients, the RMgenotype of CYP2C19 tended to increase risk of aggressive manifestation (OR=2.89, 95%CI=0.76-11.25, P-value= 0.07), compared with non RM genotype carriers. Conclusions: CYP2C19 genotype IM was the most commongenotype in Thai patients with chronic HBV infection. In addition, genotype RM could be an associated factorfor aggressive presentation in HCC related to chronic HBV infection.     

Independent and Additive Interaction Between Tumor Necrosis Factor β +252 Polymorphisms and Chronic Hepatitis B and C Virus Infection on Risk and Prognosis of Hepatocellular Carcinoma: a Case-Control Study

To assess the contribution of tumor necrosis factor (TNF)β +252 polymorphisms to risk and prognosis ofhepatocellular carcinoma (HCC), we enrolled 150 pairs of sex- and age-matched patients with HCC, patientswith cirrhosis alone, and unrelated healthy controls. TNFβ +252 genotypes were determined by polymerasechain reaction with restriction fragment length polymorphism. Multivariate analysis indicated that TNFβ G/Ggenotype [odds ratio (OR), 3.64; 95%CI, 1.49-8.91], hepatitis B surface antigen (OR, 16.38; 95%CI, 8.30-32.33),and antibodies to hepatitis C virus (HCV) (OR, 39.11; 95%CI, 14.83-103.14) were independent risk factors forHCC. There was an additive interaction between TNFβ G/G genotype and chronic hepatitis B virus (HBV)/HCVinfection (synergy index=1.15). Multivariate analysis indicated that factors associated with TNFβ G/G genotypeincluded cirrhosis with Child-Pugh C (OR, 4.06; 95%CI, 1.34-12.29), thrombocytopenia (OR, 6.55; 95%CI,1.46-29.43), and higher serum α-fetoprotein concentration (OR, 2.53; 95%CI, 1.14-5.62). Patients with TNFβG/G genotype had poor cumulative survival (p=0.005). Cox proportional hazard model indicated that TNFβ G/Ggenotype was a biomarker for poor HCC survival (hazard ratio, 1.70; 95%CI, 1.07-2.69). In conclusion, thereare independent and additive effects between TNFβ G/G genotype and chronic HBV/HCV infection on risk forHCC. It is a biomarker for poor HCC survival. Carriage of this genotype correlates with disease severity andadvanced hepatic fibrosis, which may contribute to a higher risk and poor survival of HCC. Chronic HBV/HCVinfected subjects with this genotype should receive more intensive surveillance for early detection of HCC.     

Case-control study on hepatitis C virus (HCV) as a risk factor for hepatocellular carcinoma: the role of HCV genotypes and the synergism with hepatitis B virus and alcohol. Brescia HCC Study.

We performed a case-control study to evaluate the risk of hepatocellular carcinoma (HCC) for hepatitis C virus (HCV) infection. A total of 305 newly diagnosed HCC cases (80% males) and 610 subjects (81% males) unaffected by clinically evident hepatic disease admitted to the 2 main hospitals in Brescia, North Italy, were recruited as cases and controls, respectively. Among the 122 HCC cases positive for HCV RNA, genotype 1b was found in 83 patients (68%), genotype 2 in 36 (29.5%) and genotype 1a in 3 (2.5%). Among the controls, 15 were infected with genotype 1b and 15 with type 2. Analysis of HCV envelope 1 nucleotide sequence among 25 cases and 8 controls infected with genotype 2 showed subtype 2c in 96% of cases and in all controls, and subtype 2a in 1 HCC case. The odds ratio (OR) for HCV RNA positivity adjusted for hepatitis B virus (HBV) markers and alcohol intake was 26.3 [95% confidence interval (CI): 15.8-44], and it was higher for genotype 1b (OR = 34.2) than type 2 (OR = 14.4). The OR for HCV RNA was 35.6 (95% CI: 14.5-87.1) when the HBV markers were all negative and 132 (15.3-890) when HBsAg positivity was present; the OR was 26.1 (95% CI: 12.6-54.0) among subjects with alcohol intake of 0-40 g/day and increased to 62.6 (23.3-168) and 126 (42.8-373) with an alcohol intake of 41-80 and >80 g/day, respectively. In conclusion, synergism was found between HCV infection and HBV infection and alcohol intake in causing HCC.     

CYP2E1 PstI/RsaI polymorphism and interaction with alcohol consumption in hepatocellular carcinoma susceptibility: evidence from 1,661 cases and 2,317 controls

Many studies have suggested that cytochrome P450 2E1 (CYP2E1) gene might be involved in the development of hepatocellular carcinoma (HCC). However, the results have been inconsistent. In this study, the authors performed a meta-analysis to clarify the association between Pst I/Rsa polymorphism in the CYP2E1 gene and HCC risk. PubMed and China National Knowledge Infrastructure were searched for eligible publications. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using fixed- or random-effects model. Fifteen studies (1,661 HCC cases and 2,317 controls) were identified for the data analysis. The overall result showed that there was no statistically significant association between CYP2E1 Pst I/Rsa polymorphism and HCC risk (c2/c2 vs. c1/c1, OR = 0.73, 95% CI 0.50-1.06; c1/c2 vs. c1/c1, OR = 1.00, 95% CI 0.76-1.33; c2/c2+ c1/c2 vs. c1/c1, OR = 0.99, 95% CI 0.77-1.26; c2/c2 vs. c1/c2+ c1/c1, OR = 0.73, 95% CI 0.50-1.06). Further stratified analyses indicated that the habitual alcohol drinkers with c2 alleles were more likely to develop HCC (OR = 1.73, 95% CI 1.19-2.51), compared with the non-habitual drinkers with c1 homozygote. The meta-analysis indicated that CYP2E1 Pst I/Rsa polymorphism was not associated with HCC risk, while the interaction between Pst I/Rsa polymorphism and alcohol consumption increased the risk of HCC.     

Alcohol Dehydrogenase-2 and Aldehyde Dehydrogenase-2 Genotypes,Alcohol Drinking and the Risk for Stomach Cancer in Chinese Males

Objective: To investigate the relationship among alcohol dehydrogenase-2 (ADH2) and aldehyde dehydrogenase-2 (ALDH2) genetic polymorphisms, alcohol consumption, and the susceptibility of stomach cancer in Chinese males. Methods: Three hundred and eighty-two stomach cancer patients and 382 healthy controls from Taixing and Changshu city of Jiangsu province were enrolled in this study. ADH2 and ALDH2 genotypes were examined by PCR and denaturing high-performance liquid chromatography (DHPLC). Unconditional logistic regression was used to calculate the odds ratios (OR) and 95% confidence intervals (95% CI). Results: (1) In no drinkers, compared with ALDH2G/G carriers, ALDH2 G/A (OR=1.67, 95%CI: 1.01-2.78) carriers showed a significantly elevated risk of developing stomach cancer. No association was found between ADH2 genotypes and risk of stomach cancer. (2) ALDH2 A allele carriers with cumulative amount of alcohol consumption ≥2.5 (Kg * years) were at a higher risk of developing stomach cancer compared with those with cumulative amount of alcohol consumption <2.5Kg (Kg * years) (OR=2.72, 95%CI:0.89-8.31) and ALDH2 G/G carriers with cumulative amount of alcohol consumption <2.5 (Kg * years) (OR=2.46, 95%CI=0.90-6.72) or ≥2.5 (Kg * years) (OR=2.53, 95%CI=0.86-7.49). (3) Compared with individuals with ADH2 A/A and ALDH2 G/G genotypes, ADH2 G and ALDH2 A allele carriers were not at a high risk of developing stomach cancer, with regard to the status of alcohol consumption, and even cumulative amount of alcohol consumption ≥1.5 (Kg * years) (OR =1.65, 95%CI:0.56-4.82). Conclusion: ADH2 and ALDH2 polymorphisms and alcohol drinking may not play an important role in the development of stomach cancer in Chinese males.     

Updated Meta-analysis of the Association Between CYP2E1 RsaI/PstI Polymorphisms and Lung Cancer Risk in Chinese Population

Background: A number of studies have reported relationships of CYP2E1 RsaI/PstI polymorphisms with susceptibility to lung cancer in Chinese population. However, the epidemiologic results have been conflictive rather than conclusive. The purpose of this study was to address the associations of CYP2E1 RsaI/PstI polymorphisms with lung cancer risk in Chinese population comprehensively. Materials and Methods: Systematic searches were conducted in the PubMed, Science Direct, Elsevier, CNKI and Chinese Biomedical Literature Databases. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of association. Results: Overall, we observed a decreased lung cancer risk among subjects carrying CYP2E1 RsaI/PstI c1/c2 and c1/c2+c2/c2 genotypes (OR=0.76, 95%CI: 0.64-0.90 and OR=0.78, 95%CI: 0.66-0.93, respectively), as compared with subjects carrying the c1/c1 genotype. In subgroup analysis, we observed a decreased lung cancer risk among c1/c2 carriers in hospital-based studies (OR=0.81, 95%CI: 0.68-0.98) and among carriers with c1/c2 and c1/c2+c2/c2 genotypes in population-based studies(OR=0.57, 95%CI: 0.42-0.79 and OR=0.58, 95%CI: 0.43-0.79, respectively), as compared with subjects carrying the c1/c1 genotype. Limiting the analysis to studies with controls in Hardy-Weinberg equilibrium (HWE), we similarly observed a decreased lung cancer risk among c1/c2 and c1/c2+c2/c2 carriers (OR=0.73, 95%CI: 0.60-0.88 and OR=0.73, 95%CI: 0.60-0.88, respectively), as compared with c1/c1. Conclusions: Our results suggested that CYP2E1 RsaI/PstI c1/c2 and c1/c2+c2/c2 variants might be a protective factor for developing lung cancer in Chinese population. Further well-designed studies with larger sample size are required to verify our findings.     

Eight-year follow-up of the 90,000-person Haimen City cohort: I. Hepatocellular carcinoma mortality, risk factors, and gender differences.

In an 8-year follow-up of a prospective cohort study in Haimen City, China, we sought to identify hepatocellular carcinoma (HCC) risk factors in addition to hepatitis B virus (HBV) infection. Two cohorts of adults between ages 25 and 64 years at study entry were followed from 1992-1993 to 2000. The male cohort included 58,545 men, 15.0% of whom were HBV carriers. The female cohort included 25,340 women, 10.7% of whom were HBV carriers. 434,718 person-years of follow-up were accumulated, and 1092 deaths from HCC occurred. The relationship of potential risk factors measured at study entry to HCC mortality was analyzed using Cox proportional hazards models. For males, HCC mortality was significantly associated with HBV infection [relative risk (RR) 18.8; 95% confidence interval (CI), 15.7-22.5], history of acute hepatitis (RR, 2.3; 95% CI, 2.0-2.7), family history of HCC (RR, 2.3; 95% CI, 1.9-2.7), and occupation as a peasant (RR, 1.5; 95% CI, 1.3-1.8). For females, HCC mortality was significantly associated with HBV infection (RR, 33.5; 95% CI, 17.1-65.5) and acute hepatitis history (RR, 4.7; 95% CI, 3.0-7.5). HCC risk was not significantly associated with alcohol consumption, water source, or staple foods in either sex. There was no association with smoking in males, but there was a positive association for females. Environmental and genetic risk factors besides HBV infection play a significant role in HCC mortality in this extremely high-risk population. Gender differences in HCC mortality and known risk factors are substantial and warrant further study. Identification of risk factors amenable to intervention should be a high priority in the prevention of HCC.     

Functional RsaI/PstI Polymorphism in Cytochrome P450 2E1 Contributes to Bladder Cancer Susceptibility: Evidence from a Meta-analysis

Background: Cytochrome P450 2E1 (CYP2E1) might be involved in the development of bladder cancer. However, previous studies of any association between CYP2E1 RsaI/PstI polymorphism and bladder cancer risk have yielded conflicting results. In this study, we performed a more precise estimation of the relationship by a meta-analysis based on the currently available evidence from the literature. Method: To assess the effect of CYP2E1 RsaI/PstI polymorphism on bladder cancer susceptibility, a meta-analysis of 6 available studies with 1,510cases and 1,560 controls were performed through Feb 2014. Summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were used to estimate the strength of association for CYP2E1 RsaI/PstI polymorphism under different genetic models. Results: When available studies were pooled into the meta-analysis, we found that the C1C2 and C2C2 genotypes of CYP2E1 RsaI/PstI polymorphism significantly decreased bladder cancer risk under different genetic models (heterozygote: OR=0.766, 95%CI=0.613-0.957, POR=0.019; homozygote: OR=0.51, 95%CI=0.303- 0.858, POR=0.011; dominant: OR=0.733, 95%CI=0.593-0.905, POR=0.004; recessive: OR=0.565, 95%CI=0.337-0.947, POR=0.030). Subgroup analysis indicated that C2C2 genotype was significantly associated with decreased bladder cancer risk under the homozygote genetic model in Caucasians. There was no evidence of heterogeneity or publication bias. Conclusions: The current meta-analysis suggested that the CYP2E1 RsaI/PstI polymorphism might be associated with bladder cancer susceptibility, especially in Caucasians. Further studies are needed to validate the above conclusion.     

CYP2E1 RsaI/PstI Polymorphism and Liver Cancer Risk among East Asians: a Huge Review and Meta-analysis

Published data on any association between the CYP2E1 RsaI/PstI (c1/c2) polymorphism and liver cancer riskamong east Asians are inconclusive. The aim of this Human Genome Epidemiology (HuGE) review and metaanalysiswas to derive a more precise estimation of the relationship. A literature search of Pubmed, Embase, Webof science and CBM databases from inception through July 2012 was conducted. Twelve case-control studies wereincluded with a total of 1,552 liver cancer cases and 1,763 healthy controls. Crude odds ratios (ORs) with 95%confidence intervals (CIs) were used to assess the strength of association under five genetic models. When all theeligible studies were pooled into the meta-analysis, the results showed that the c2 allele and the c2 carrier (c2/c2+ c2/c1) of RsaI/PstI polymorphism were associated with decreased risk of liver cancer among east Asians (c2vs. c1: OR = 0.75, 95%CI: 0.59-0.95, P = 0.016; c2/c2 + c2/c1 vs. c1/c1: OR = 0.76, 95%CI: 0.58-1.00, P = 0.050).In the stratified analysis by country, significant associations were observed between RsaI/PstI polymorphismand decreased risk of liver cancer among the Chinese population (c2 vs. c1: OR = 0.70, 95%CI: 0.54-0.91, P =0.007; c2/c2 + c2/c1 vs. c1/c1: OR = 0.72, 95%CI: 0.54-0.95, P = 0.020), but not among Japanese and Koreanpopulations. Results from the current meta-analysis indicates that the c2 allele of CYP2E1 RsaI/PstI (c1/c2)polymorphism may be a protective factor for HCC among east Asians, especially among China populations.     

Genetic variation in alcohol dehydrogenase (ADH1A, ADH1B, ADH1C, ADH7) and aldehyde dehydrogenase (ALDH2), alcohol consumption and gastric cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort

Studies that have examined the association between alcohol consumption and gastric cancer (GC) risk have been inconsistent. We conducted an investigation of 29 genetic variants in alcohol metabolism loci (alcohol dehydrogenase, ADH1 gene cluster: ADH1A, ADH1B and ADH1C; ADH7 and aldehyde dehydrogenase, ALDH2), alcohol intake and GC risk. We analyzed data from a nested case-control study (364 cases and 1272 controls) within the European Prospective Investigation into Cancer and Nutrition cohort. Single nucleotide polymorphisms (SNPs) were genotyped using a customized array. We observed a statistically significant association between a common 3'-flanking SNP near ADH1A (rs1230025) and GC risk [allelic odds ratio (OR)(A v T) = 1.30, 95% confidence interval (CI) = 1.07-1.59]. Two intronic variants, one in ADH1C (rs283411) and one in ALDH2 (rs16941667), also were associated with GC risk (OR(T v C) = 0.59; 95% CI = 0.38-0.91 and OR(T v C) = 1.34; 95% CI = 1.00-1.79, respectively). Individuals carrying variant alleles at both ADH1 (rs1230025) and ALDH2 (rs16941667) were twice as likely to develop GC (OR(A+T) = 2.0; 95% CI = 1.25-3.20) as those not carrying variant alleles. The association between rs1230025 and GC was modified by alcohol intake (<5 g/day: OR(A) = 0.89, 95% CI = 0.57-1.39; ≥5 g/day: OR(A) = 1.45, 95% CI = 1.08-1.94, P-value = 0.05). The association was also modified by ethanol intake from beer. A known functional SNP in ADH1B (rs1229984) was associated with alcohol intake (P-value = 0.04) but not GC risk. Variants in ADH7 were not associated with alcohol intake or GC risk. In conclusion, genetic variants at ADH1 and ALDH2 loci may influence GC risk, and alcohol intake may further modify the effect of ADH1 rs1230025. Additional population-based studies are needed to confirm our results.     

Relationship between alcohol drinking, ADH2 and ALDH2 genotypes, and risk for hepatocellular carcinoma in Japanese

The polymorphism in the ALDH2 gene plays a central role in Asian alcohol hypersensitivity and has been associated with the risk for esophageal cancer. In the present study, we attempted to examine associations between the ADH2 and ALDH2 polymorphisms, alcohol drinking and hepatocellular carcinoma (HCC) development in a case-control study in Japan. One hundred and two patients with HCC (85 males and 17 females) and 125 control subjects (101 males and 24 females) were enrolled in the study. Higher cumulative amounts of alcohol consumption (drink-years of > or = 40 drinks/day x year) showed a significant association with HCC development (odds ratio, OR = 2.7; 95% CI = 1.3-5.5, adjusted for age and smoking). By contrast, we could find no association of the ALDH2 genotypes with HCC development (adjusted OR for ALDH2*1/*2 = 1.1; 95% CI = 0.6-2.1). Likewise, the ADH2 genotypes were not associated with HCC development (adjusted OR for ADH2*2/*2 = 0.8; 95% CI = 0.5-1.5). The present results do not support a contribution of acetaldehyde, an active metabolite of ethanol, to HCC development and rather indicate a direct involvement of ethanol in hepatocarcinogenesis.     

Association of CYP1A1, CYP1A2, GSTM1 and NAT2 gene polymorphisms with colorectal cancer and smoking.

We investigated CYP1A1*2A, CYP1A1*2C, CYP1A2*1C, CYP1A2*1F, GSTM1 and NAT2 gene polymorphisms, involving enzymes which metabolize many carcinogens, with reference to colorectal cancer risk. The distribution of these genotypes was not associated with risk overall. However, the CYP1A1*2A T/C genotype showed a significant association with colorectal cancer risk in never-smokers (odds ratio [OR], 3.06; 95% confidence interval [95% CI], 1.11-8.40; p = 0.030). The risk of the NAT2 rapid genotype in never-smokers was also statistically significantly increased (OR, 5.38; 95%CI, 1.80-16.1; p = 0.003). Furthermore, the joint effects of NAT2 rapid plus other genotypes were associated with colorectal cancer overall (OR, 3.12; 95%CI, 1.15-8.51; p = 0.026, for NAT2 rapid plus combined CYP1A1*2C Ile/Val and Val/Val, OR, 3.25; 95%CI, 1.09-9.74; p = 0.035, for NAT2 rapid plus CYP1A2*1C G/G, and OR, 4.20; 95%CI, 1.09-16.1; p = 0.037, for NAT2 rapid plus GSTM1 null, respectively). In never-smokers, the joint effects of NAT2 rapid plus other genotypes were remarkable (OR, 15.9; 95%CI, 1.87-135.8; p = 0.011, for NAT2 rapid plus combined CYP1A1*2A T/C and C/C, OR, 5.71; 95%CI, 1.49-21.9; p = 0.011, for NAT2 rapid plus combined CYP1A1*2C Ile/Val and Val/Val, and OR, 9.14; 95%CI, 2.05-40.7; p = 0.004, for NAT2 rapid plus CYP1A2*1F A/A, respectively). The joint effect of CYP1A2*1F A/A plus CYP1A2*1C G/G genotypes was also increased in never-smokers (OR, 6.16; 95%CI, 1.26-30.1; p = 0.025). Our findings suggest that the CYP1A1*2A T/C and NAT2 rapid genotypes is associated with colorectal cancer susceptibility without smoking exposure. These results also indicate that the NAT2 in combination with CYP1A1*2C, CYP1A2*1C, or GSTM1 genotypes may strongly confer susceptibility to colorectal cancer. In particular, the combination of NAT2 plus CYP1A1*2A, CYP1A1*2C, or CYP1A2*1F genotypes, and that of CYP1A2*1F plus CYP1A2*1C genotype may define a group of persons who are genetically susceptible to colorectal cancer in never smokers.     

Esophageal squamous cell carcinoma and ALDH2 and ADH1B polymorphisms in Chinese females

Aim: Alcohol dehydrogenase-IB (ADH1B) and aldehyde dehydrogenase-2 (ALDH2) are the key enzymes for elimination of ethanol and acetaldehyde, the latter being an established animal carcinogen produced after drinking. In this study, we aimed to evaluate the contribution of ADH1B and ALDH2 polymorphisms to the risk of esophageal squamous cell (ESCC) in Chinese females. Methods: A total of 81 pathologically-proven female ESCC cases and 162 female controls were recruited from the Affiliated Hospital of Medical College of Armed Police Forces of PRC in China. ADH1B and ALDH2 polymorphisms were genotyped using PCR-CTPP. Results: Compared with those with ADH1B*2/*2, individuals with ADH2*1/*2 and ADH2*1/*1 had 1.47 and 2.36-fold, respectively, increased risk of developing ESCC (95%CI=0.84-2.58, 95%CI=1.14-5.79) after adjusting for alcohol consumption and other covariates. Significantly increased risk was also noted among subjects with ALDH2*1/*2 (adjusted OR=3.24, 95%CI=1.45-5.36), when compared to those with ALDH2*1/*1. Risk was greater in heavy drinking females carrying ADH1B *1/*1 or ALDH2*1/*2 genotypes compared to those with ADH1B*2 and ALDH2*1/*1. Moreover, we found a significant trend of ESCC risk with alcoholic consumption in women with ALDH2*1/*2. Conclusion: Chinese women with ADH1B *1/*1 or ALDH2*1/*2 have elevated risk of ESCC similarly to men. Women with inactive ADH1B and ALDH2 should reduce drinking and increase their intake of vegetable and fruit to prevent development of esophageal cancer.     

Risk Factors for Esophageal Cancer: a Case-control Study in South-western China

Esophageal cancer is a crucial cancer in China. Yanting in Sichuan Province was a key area with highest esophageal ‍cancer mortality in China, but little evidence on esophageal cancer risk factors has been reported for this area and ‍the etiology remains unclear. To clarify risk factors, a 1:1 matched case-control study was conducted. Totals of 185 ‍eligible esophageal cancer patients and 185 healthy residents matched for sex and age were recruited. Conditional ‍logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for possible risk/ ‍protective factors. All ORs were adjusted by family history of esophageal cancer and occupation, and then further ‍adjusted by other possible confounding factors. Our results showed that smoking and alcohol drinking were risk ‍factors for esophageal cancer with dose-response. The ORs (95% CI) compared with never smokers and drinkers ‍were 4.06 (1.55-10.6) and 2.49 (1.06-5.85), respectively. The OR was further increased to 8.86 (95%CI, 3.82-20.5) for ‍both smoking and drinking in combination. Eating food rapidly (OR=5.84, 95%CI, 2.05-16.7), drinking shallow ‍ground water (OR=4.18, 95%CI, 1.30-13.4) and frequent intake of picked vegetables (OR=2.12, 95%CI, 1.00-4.49) ‍appeared to increase the risk, while frequent intake of fresh fruit (OR=0.42, 95%CI, 0.19-0.89), fresh vegetables ‍(OR= 0.62, 95%CI, 0.32-1.17) and eggs (OR=0.59, 95%CI, 0.25-1.39) decreased the risk. In conclusion, smoking and ‍alcohol drinking are common in Yanting and main contributors to esophageal cancer. Consumption of fresh fruit ‍and eggs are not common and high consumption of these two foods as well as fresh vegetables may decrease the risk ‍of esophageal cancer in this area. In addition, drinking shallow ground water and eating food rapidly, as well as ‍frequent intake of pickled vegetables, are also factors increasing the risk. ‍ ‍