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.     

Intake of fatty acids and antioxidants and pancreatic cancer in a large population‐based case‐control study in the San Francisco Bay Area

There are no well‐established modifiable risk factors for pancreatic cancer except smoking. Some dietary factors have been associated with pancreatic cancer risk and require further study. We examined the associations among intake of specific fatty acids and antioxidants and risk of pancreatic cancer in a large population‐based case‐control study in the San Francisco Bay Area. Unconditional logistic regression models were used to compute odds ratios (ORs) and 95% confidence intervals (CI) as estimates of relative risk. Positive associations were observed for high levels of the 8 individual saturated fatty acids (4th vs. 1st quartile: ORs ranged from 1.6 to 2.6; all p_trend < 0.01), monounsaturated palmitoleic and oleic fatty acids [OR = 1.6 (95% CI: 1.2–2.1) and 1.4 (95% CI: 1.1–1.9); both p_trend < 0.01], and polyunsaturated linolenic acid [OR = 1.5 (95% CI: 1.1–2.0); p_trend = 0.02]. Inverse associations were observed for high levels of gadolic acid [4th vs. 1st quartile: OR = 0.68 (95% CI: 0.50–0.92); p_trend = 0.007] and omega‐3 fatty acids [≥0.85 g/day vs. 1st quartile: OR = 0.47 (95% CI: 0.25–0.90)]. An inverse association was also observed for high total intake of vitamin C [4th vs. 1st quartile: OR = 0.69 (95% CI: 0.51–0.94); p_trend = 0.004] and of vitamin E [OR = 0.67 (95% CI: 0.49–0.92); p_trend = 0.01]. Although similar decreased risks were also observed for high supplemental intake of these 2 vitamins (both p_trend < 0.01), no association was observed for intake from food alone. These results support the hypotheses that a high intake of saturated and certain monounsaturated fatty acids may increase the risk of pancreatic cancer, whereas greater intake of omega‐3 fatty acids, vitamins C and E may reduce the risk.     

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.     

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.     

Common genetic variations of the cytochrome P450 1A1 gene and risk of hepatocellular carcinoma in a Chinese population

Cytochrome P450 1A1 is a major enzyme in the bioactivation of exogenous procarcinogens of hepatocellular carcinoma (HCC). However, the contribution of common genetic variants in CYP1A1 to the HCC risk in Chinese populations has not been thoroughly investigated. In this study, we examined the association between HCC and four selected tagging single nucleotide polymorphisms (SNPs) of CYP1A1, and the risk of CYP1A1 haplotypes/diplotypes in 1006 pathologically confirmed HCC patients and 1015 cancer-free controls, from a Han Chinese population. Haplotypes/diplotypes were constructed from observed genotypes using the Haplo.Stats program. Relative risk was estimated by using multivariable logistic regression method. To summarise, we detected an increased HCC risk in rs4646421 variant carriers (OR 1.30, 95% CI 1.05–1.61) and rs2198843 variant carriers (OR 1.33, 95% CI 1.05-1.69), and a reduced risk of HCC (OR 0.70. 95% CI 0.52–0.94) associated with homozygote carriers of rs4886605 variant. These association signals were also observed in non-smokers with rs4646421 (OR 1.56, 95% CI 1.16–2.08) and rs4886605 (OR 0.61, 95% CI 0.40–0.91). Compared to the most common CYP1A1 haplotype CCAG, the haplotype TTGC conferred an increased risk of HCC (OR 1.26, 95% CI 1.04–1.52). Similarly, the TTGC/TTGC diplotype conferred an increased risk of HCC compared with diplotype CCAG/CCAG (OR 2.06, 95% CI 1.23–3.45, P = 0.006). Interestingly, the diplotype TTAC/CCAG also conferred an increased risk of HCC (OR 1.76, 95% CI 1.22–2.54, P = 0.003). Our results suggested that common genetic variants in CYP1A1 may modulate the risk of developing HCC in the study population, particularly in non-smokers. However, our findings need to be validated in at least one independent study of Han Chinese population.     

CYP1A1 and CYP2E1 genotypes and risk of esophageal squamous cell carcinoma in a high-incidence region,Kashmir

The study analyzed the relationship between genetic polymorphisms of phase I xenobiotic metabolizing enzymes, cytochromes P450 (CYP) 1A1 and CYP2E1 and esophageal squamous cell carcinoma (ESCC) in Kashmir, India. The different genotypes of CYP1A1 and CYP2E1 were analyzed by polymerase chain reaction and restriction fragment length polymorphism in 526 ESCC cases and equal number of matched controls. Conditional logistic regression models were used to assess the association of various genotypes with ESCC, gene–gene, and gene–environment interactions. High risk of ESCC was found in participants who carried CYP1A1 Val/Val genotype (OR?=?2.87; 95 % CI?=?1.00–8.44) and the risk increased in such individuals when c1/c1 of CYP2E1 genotype was also present (OR?=?5.68; 95 % CI?=?1.09–29.52). Risk due to CYP1A1 Val/Val genotype was further enhanced (OR?=?8.55; 95 % CI?=?1.86–42.20) when the analysis was limited to ever smokers. Participants who carried CYP2E1 c1/c2 genotype showed an inverse relation (OR?=?0.27; 95 % CI?=?0.17–0.43) with ESCC. The inverse association of CYP2E1 c1/c2 genotype was retained when CYP1A1 Ile/Ile was also present (OR?=?0.18; 95 % CI?=?0.09–0.32), as well as when analysis was limited to ever smokers (OR?=?0.45; 95 % CI?=?0.23–0.90). Significant interaction was found between CYP1A1 (Val/Val) and CYP2E1 (c1/c1) genotypes (OR?=?1.30; 95 % CI?=?1.12–1.51; P?=?0.001) and between CYP1A1 (Val/Val) and smoking (OR?=?1.31; 95 % CI?=?1.01–1.69; P?=?0.043). The study suggests CYP1A1 Val/Val and CYP2E1 c1/c1 genotypes are significantly associated with ESCC risk.     

N‐acetyl transferase 2 genotypes,meat intake and breast cancer risk

Heterocyclic amines (HAs) are carcinogens produced by high‐temperature cooking of meat and animal protein; metabolism of HA is influenced by polymorphisms in the N‐ acetyltransferase‐2 (NAT‐2) gene. Data from a variety of sources suggest that HA may play a role in human carcinogenesis. We examined the associations between meat intake and cooking method, acetylator genotype and breast cancer risk in a sub‐cohort of 32,826 women in the Nurses' Health Study who gave a blood sample in 1989–1990. Women who were diagnosed with breast cancer (n = 466) after blood draw and prior to June 1, 1994, were matched to 466 controls. Overall, rapid acetylators were not at increased risk of breast cancer compared with slow acetylators (multivariate OR = 1.1, 95% CI 0.8–1.5), and there were no associations between meat intake or cooking method of meat and breast cancer risk. Rapid acetylators with the highest red meat intake (one or more servings per day) were not at increased risk of breast cancer compared with slow acetylators with the lowest red meat intake (OR = 1.1, 95% CI 0.7–1.8). Frequent intake of charred meat among rapid acetylators (one or more times per week) was not associated with increased risk (OR = 1.2, 95% CI 0.6–2.3) compared with slow acetylators who ate charred meat less than once per month. We observed no significant associations for rapid acetylators who frequently consumed beef, pork or lamb cooked with high‐temperature cooking methods, such as barbecuing (OR = 0.9, 95% CI 0.4–1.9) or roasting (OR = 0.9, 95% CI 0.5–1.6). Our data suggest that HAs may not be a major cause of breast cancer, although we cannot exclude misclassification of HA intake as the reason for the lack of association. We observed no evidence of differential susceptibility to these exposures by NAT2 genotype. Int. J. Cancer 80:13–17, 1999. © 1999 Wiley‐Liss, Inc.     

Genetic polymorphisms of ALDH2 and ADH2 are not associated with risk of hepatocellular carcinoma among East Asians

The aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 2 (ADH2) genes have been implicated in the development of hepatocellular carcinoma (HCC). However, the results have been inconsistent. In this study, we performed a meta-analysis to clarify the associations between polymorphisms of ALDH2 and ADH2 genes and HCC. Published literatures from PubMed and Embase were retrieved. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model. Ten studies including 1,231 HCC cases and 1,849 controls were included in the meta-analysis of the association between ALDH2 polymorphism and HCC risk. The results indicated that ALDH2 polymorphism was not significantly associated with risk of HCC (homogeneous co-dominant model: OR = 0.99, 95% CI 0.72–1.34; heterogeneous co-dominant model: OR = 0.90, 95% CI 0.75–1.08; dominant model: OR = 0.91, 95% CI 0.70–1.18; recessive model: OR = 1.11, 95% CI 0.66–1.87). In addition, four studies including 518 cases and 607 controls were included in the meta-analysis of the association between ADH2 polymorphism and HCC risk. There was no association between ADH2 polymorphism and HCC risk (homogeneous co-dominant model: OR = 0.93, 95% CI 0.58–1.51; heterogeneous co-dominant model: OR = 1.39, 95% CI 0.87–2.23; dominant model: OR = 1.19, 95% CI 0.76–1.88; recessive model: OR = 0.91, 95% CI 0.54–1.54). Further analysis suggested that the ALDH2 polymorphism–alcohol interaction was marginally associated with HCC risk under the dominant model (OR = 2.05, 95% CI 1.01–4.17). However, the result was not robust by sensitivity analysis. The results from the present meta-analysis indicated that there was no significant association between ALDH2 polymorphism, ADH2 polymorphism, or ALDH2 polymorphism–alcohol intake interaction and HCC risk in the East Asians.     

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.     

Alcohol Dehydrogenase 3, Glutathione S-transferase M1 and T1 Polymorphisms, Alcohol Consumption and Hepatocellular Carcinoma (Italy)

Objective: The aim of this study was to investigate the role of alcohol dehydrogenase type 3 (ADH3), glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) polymorphisms in modifying hepatocellular carcinoma (HCC) risk according to alcohol intake.Methods: A hospital-based case–control study was conducted in two areas of North Italy. Two-hundred cases hospitalized for HCC and 400 controls were recruited. Genotypes were determined using PCR and the PCR/restriction fragment length polymorphism-based method.Results: There was no association of the putative risk genotypes ADH3^1-1, GSTM1 null and GSTT1 null with HCC (odds ratio [OR], 0.8; 95% confidence interval [CI], 0.5–1.3; OR, 1.0; 95% CI, 0.6–1.5; OR, 0.8; 95% CI, 0.4–1.4, respectively). A steady increase in HCC risk with increasing alcohol intake, which did not vary according to ADH3 and GSTT1 genotypes, was observed. Nevertheless, the OR for HCC due to an alcohol intake of >100 g of ethanol per day increased in subjects with GSTM1 null genotype (OR, 8.5; 95% CI, 3.9–18.6) compared to GSTM1 non-null genotype (OR, 4.5; 95% CI, 2.0–10.0).Conclusions: ADH3^1-1 and GSTT1 null genotypes did not modify the risk of HCC due to alcohol intake whereas an influence of GSTM1 null genotype for high ethanol consumption was suggested.     

Fruit and vegetable consumption,Helicobacter pylori antibodies,and gastric cancer risk: A pooled analysis of prospective studies in China,Japan, and Korea

Epidemiological findings on the association between fruit and vegetable consumption and gastric cancer risk remain inconsistent. The present analysis included 810 prospectively ascertained non‐cardia gastric cancer cases and 1,160 matched controls from the Helicobacter pylori Biomarker Cohort Consortium, which collected blood samples, demographic, lifestyle, and dietary data at baseline. Conditional logistic regression adjusting for total energy intake, smoking, and H. pylori status, was applied to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for gastric cancer risk across cohort‐ and sex‐specific quartiles of fruit and vegetable intake. Increasing fruit intake was associated with decreasing risk of non‐cardia gastric cancer (OR = 0.71, 95% CI: 0.52–0.95, p trend = 0.02). Compared to low‐fruit consumers infected with CagA‐positive H. pylori, high‐fruit consumers without evidence of H. pylori antibodies had the lowest odds for gastric cancer incidence (OR = 0.12, 95% CI: 0.06–0.25), whereby the inverse association with high‐fruit consumption was attenuated among individuals infected with CagA‐positive H. pylori (OR = 0.82, 95% CI: 0.66–1.03). To note, the small number of H. pylori negative individuals does influence this finding. We observed a weaker, nondose‐response suggestion of an inverse association of vegetable intake with non‐cardia gastric cancer risk. High fruit intake may play a role in decreasing risk of non‐cardia gastric cancer in Asia.     

Telomere length,oxidative damage,antioxidants and breast cancer risk

Telomeres play a critical role in maintaining the integrity and stability of the genome, and are susceptible to oxidative damage after telomere shortening to a critical length. In the present study, we explored the role of white blood cell DNA telomere length on breast cancer risk, and examined whether urinary 15‐F₂‐isoprostanes (15‐F_2t‐IsoP) and 8‐oxo‐7,8‐dihydrodeoxyguanosine (8‐oxodG) or dietary antioxidant intake modified the relationship between telomere length and breast cancer risk. A population‐based case–control study—the Long Island Breast Cancer Study Project—was conducted among 1,067 cases and 1,110 controls. Telomere length was assessed by quantitative PCR. Overall, the mean levels of telomere length (T/S ratio), 15‐F_2t‐IsoP and 8‐oxodG were not significantly different between cases and controls. Among premenopausal women only, carrying shorter telomeres (Q3 and Q4), as compared with the longest (Q1), was associated with significantly increased breast cancer risk. Age‐adjusted OR and 95% CI were 1.71 (1.10–2.67) and 1.61 (1.05–2.45). The 5‐F_2t‐IsoP and 8‐oxodG biomarkers did not modify the telomere–breast cancer association. A moderate increase in breast cancer risk was observed among women with the shortest telomeres (Q4) and lower dietary and supplemental intake of β‐carotene, vitamin C or E intake [OR (95% CI) = 1.48 (1.08–2.03), 1.39 (1.01–1.92) and 1.57 (1.14–2.18), respectively], although the trend test exhibited statistical significance only within the lower vitamin E intake subgroup (p_trend = 0.01). These results provided the strongest evidence to date that breast cancer risk may be affected by telomere length among premenopausal women or women with low dietary intake of antioxidants or antioxidant supplements. © 2008 Wiley‐Liss, Inc.     

Associations of dietary folate,Vitamins B6 and B12 and methionine intake with risk of breast cancer among African American and European American women

African American (AA) women are more likely than European American (EA) women to be diagnosed with breast cancer at younger ages and to develop poor prognosis tumors. However, these racial differences are largely unexplained. Folate and other methyl‐group nutrients may be related to breast carcinogenesis, but few studies have examined these associations in AA populations. We examined the associations of dietary intake of these nutrients with breast cancer risk overall, by menopausal and estrogen receptor (ER) status among 1,582 AA (749 cases) and 1,434 EA (744 cases) women using data from a case–control study, the Women's Circle of Health Study. Unconditional multivariable logistic regression models were used to compute odds ratios (ORs) and 95% confidence intervals (CIs) for the association of each nutrient and breast cancer risk. In AA women, inverse associations were observed for natural food folate intake among premenopausal women (fourth vs. first quartile: OR = 0.57, 95% CI, 0.33–1.00; p for trend = 0.06) and for ER‐positive tumors (fourth vs. first quartile: OR = 0.58, 95% CI, 0.36–0.93; p for trend = 0.03), whereas in EA women, a positive association was observed for intake of synthetic folate (fourth vs. first quartile: OR = 1.53, 95% CI, 1.06–2.21; p for trend = 0.03). Our findings suggest that natural food folate intake is inversely associated with breast cancer risk and that this association may vary by race, menopausal status or ER status. The finding of an increased risk observed among EA women with the highest intake of synthetic folate from fortified foods warrants further investigation.     

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.     

IL12 polymorphisms,HBV infection and risk of hepatocellular carcinoma in a high‐risk Chinese population

To investigate the association between the potentially functional polymorphisms in IL12A and IL12B, HBV infection and risk of hepatocellular carcinoma in a Chinese population, we genotyped three polymorphisms, rs568408 (3′UTR G>A), rs2243115 (5′UTR T>G) in IL12A and rs3212227 (3′UTR A>C) in IL12B in a case–control study of 869 hepatocellular carcinoma (HCC) cases and 891 cancer‐free controls. We found that the IL12A rs568408 GA/AA variant genotypes were associated with a significantly increased risk of HCC (adjusted odds ratio (OR) = 1.53, 95% confidence interval (CI) = 1.17–2.00), compared with the wild‐type GG homozygote. In the stratified analyses, the increased risk of HCC associated with rs568408 GA/AA was more evident in patients who were negative for HBsAg (adjusted OR = 1.71, 95% CI = 1.23–2.39). However, no significant associations between IL12A rs2243115 T/G, IL12B rs3212227 A/C and risk of HCC were observed. Our findings indicate that IL12A rs568408 may contribute to the risk of HCC and modify HCC risk associated with HBV infection.     

Association of HLA‐DRB1, interleukin‐6 and cyclin D1 polymorphisms with cervical cancer in the Swedish population—A candidate gene approach

High‐risk human papillomavirus (hrHPV) infection is the major risk factor for cervical cancer (CxCa). The role of genetic susceptibility in the disease has been suggested, but the existing data lack consistency. We conducted a nested case‐control study on 973 CxCa cases and 1,763 matched controls, from two Swedish population‐based cohorts to examine the association of common genetic variants with CxCa risk. Human leukocyte antigen (HLA) alleles and 24 other polymorphisms in 14 genes were selected on the basis of reported association or mechanistic plausibility with an HPV infection or cervical cancer development. Genotyping was conducted using multiplex PCR and Luminex technology. A significant association of CxCa with various polymorphisms was observed: rs1800797 in the IL‐6 gene (odds ratio [OR] = 0.88, 95% confidence intervals [CI]: 0.79–0.99); rs1041981 in the LTA gene (OR = 0.87, 95% CI: 0.78–0.98), and rs9344 in the CCND1 gene (OR = 1.14, 95% CI: 1.02–1.27), for those individuals carrying the rare allele. Additionally, the alleles 0401 and 1501 of the HLA class II DRB1 locus were associated with an increased risk (OR = 1.23, 95% CI: 1.04–1.45 and OR = 1.29, 95% CI: 1.11–1.50, respectively), and allele 1301 was associated with decreased risk (OR = 0.59, 95% CI: 0.47–0.73). The effects of CCND1 and the HLA*DRB1 alleles were independent of the effect of smoking. We did not find any association of risk with polymorphisms in genes related to the innate immune system. In conclusion, our study provides evidence for genetic susceptibility to CxCa due to variations in genes involved in the immune system and in cell cycle. © 2009 UICC     

CYP2E1 T7632A and 9-bp insertion polymorphisms and colorectal cancer risk: a meta-analysis based on 4,592 cases and 5,918 controls

Previous studies suggest that genetic factors play important roles in the development of colorectal cancer. CYP2E1 T7632A and 9-bp insertion polymorphisms may influence the risk of colorectal cancer, but published results are conflicting. We therefore conducted a meta-analysis comprising 9 case–control studies with 4,592 cases and 5,918 controls. Odds ratios (ORs) with 95 % confidence interval (95 % CI) were used to assess the strength of the associations of CYP2E1 T7632A and 9-bp insertion polymorphisms with colorectal cancer. For CYP2E1 T7632A polymorphism, meta-analysis showed that there was no significant association between the CYP2E1 T7632A polymorphism and colorectal cancer risk under all contrast models (A vs. T: OR?=?1.06, 95 % CI 0.88–1.29, P?=?0.528; AA vs. TT: OR?=?0.85, 95 % CI 0.61–1.19, P?=?0.351; AA/TA vs. TT: OR?=?1.08, 95 % CI 0.87–1.34, P?=?0.484; and AA vs. TT/TA: OR?=?0.87, 95 % CI 0.62–1.21, P?=?0.395). For CYP2E1 96-bp insertion polymorphism, meta-analysis showed that there was a significant association between the CYP2E1 96-bp insertion polymorphism and colorectal cancer risk under the allele contrast model and the dominant contrast model (for the allele contrast model: OR?=?1.20, 95 % CI 1.06–1.36, P?=?0.005; for the dominant contrast model: OR?=?1.25, 95 % CI 1.07–1.45, P?=?0.005). Subgroup analysis by race suggested that there was an obvious association between the CYP2E1 96-bp insertion polymorphism and colorectal cancer risk in Asians under the codominant contrast model. In conclusion, our meta-analysis demonstrates that there is a significant association between the CYP2E1 96-bp insertion polymorphism and colorectal cancer risk, and CYP2E1 9-bp insertion polymorphism is a risk factor for developing colorectal cancer.     

Xenobiotic-Metabolizing gene polymorphisms and ovarian cancer risk

Because selected xenobiotic‐metabolizing enzymes process pro‐carcinogens that could initiate ovarian carcinogenesis, we hypothesized that single nucleotide polymorphisms (SNPs) in the genes encoding xenobiotic‐metabolizing enzymes are associated with risk of ovarian cancer. Cases with invasive epithelial ovarian cancer (N = 1,571 including 956 of serous sub‐type) and controls (N = 2,046) from three studies were genotyped at 11 SNPs in EPHX1, ADH4, ADH1A, NQO2, NAT2, GSTP1, CYP1A1, and NQO1, following an initial SNP screen in a subset of participants. Logistic regression analysis of genotypes obtained via Illumina GoldenGate and Sequenom iPlex technologies revealed the following age‐ and study‐adjusted associations: EPHX1 rs1051740 with increased serous ovarian cancer risk [per‐allele odds ratio (OR) 1.17, 95% confidence interval (95% CI) 1.04–1.32, P = 0.01), ADH4 r1042364 with decreased ovarian cancer risk (OR 0.90, 95% CI: 0.81–1.00, P = 0.05), and NQO1 rs291766 with increased ovarian cancer risk (OR 1.11, 95% CI: 1.00–1.23, P = 0.04). These findings are consistent with prior studies implicating these genes in carcinogenesis and suggest that this collection of variants is worthy of follow‐up in additional studies. © 2010 Wiley‐Liss, Inc.     

Low‐risk variants FGFR2, TNRC9 and LSP1 in German familial breast cancer patients

To validate common low‐risk variants predisposing for breast cancer (BC) in a large set of BRCA1/2 negative familial or genetically enriched cases from Germany, we genotyped 1,415 cases and 1,830 healthy women by MALDI‐TOF in 105 candidate SNPs. Significantly higher ORs than previously reported for heterozygous unselected cases were found for the minor allele in FGFR2 (OR = 1.43, 95% CI 1.30‐1.59, p‐value = 1.24 × 10⁻¹²) and for TNRC9 (OR = 1.33, 95% CI 1.19‐1.46, p‐value = 1.54 × 10⁻⁷). Most intriguing, however, were the ORs for homozygous carriers from high‐risk families for FGFR2 (OR = 2.05, 95% CI 1.68–2.51, LSP1 (OR = 0.49, 95% CI 0.28–0.86) and TNRC9 (OR = 1.62, 95% CI 1.27–2.07). Moreover, the additional validation of 99 CGEMS‐SNPs identified putative novel susceptibility alleles within the LSP1 gene (OR = 0.73, 95% CI 0.61–0.87, p‐value = 5.23 × 10⁻⁴⁾. Finally, we provide evidence for the first time that a low‐risk variant located at 6q22.33 (rs6569479) is associated with estrogen receptor negative BC in familial cases (OR = 1.33, 95% CI 1.06–1.66; p‐value = 0.012). Our data confirm the impact of the previously identified susceptibility loci and provide preliminary evidence for novel susceptibility loci in familial BC cases and correlate them to specific histopathological subtypes defined by estrogen receptor status.