Gene–environment interactions between alcohol drinking and the MTHFR C677T polymorphism impact on esophageal cancer risk: results of a case–control study in Japan

Chun-Xia Yang 1, 2, Keitaro Matsuo 2, *, Hidemi Ito 2, Masayuki Shinoda 3, Shunzo Hatooka 4, Kaoru Hirose 2, Kenji Wakai 2, Toshiko Saito 2, Takeshi Suzuki 2, 6, Takako Maeda 5 and Kazuo Tajima 2

1 Department of Epidemiology, Huaxi Public Health School, Sichuan University, Chengdu 610041, China, 2 Division of Epidemiology and Prevention, 3 Department of Rehabilitation Service, 4 Department of Thoracic Surgery and 5 Department of Clinical Laboratory, Aichi Cancer Center, Nagoya, Japan and 6 Department of Internal Medicine and Molecular Science, Nagoya City University Graduate School of Medical Science, Nagoya Aichi, Japan

* To whom correspondence should be addressed at: Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. Fax: +81 52 763 5233; Email: kmatsuo{at}aichi-cc.jp


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Folate takes part in two biological pathways involved in DNA methylation and synthesis, and a potential protective influence of this nutrient chemical against carcinogenicity has been recognized in several sites, including the esophagus. Therefore, the functional polymorphisms in genes encoding folate metabolizing enzymes, MTHFR C677T and MTR A2756G, might be suspected of impacting on esophageal cancer risk. We therefore conducted a matched case–control study of 165 esophageal cancer cases and 495 non-cancer controls to clarify associations among folate intake, MTHFR C677T and MTR A2756G polymorphisms, and esophageal cancer risk. Gene–environment interactions between the two polymorphisms, and drinking and smoking were also evaluated. Folate consumption and MTHFR 677TT were associated with a non-significant tendency for decreased risk while the MTR genotypes did not show any links in themselves; further, when analysis was limited to heavy drinkers, the MTHFR TT genotype significantly decreased esophageal cancer risk [odds ratio (OR) = 0.27, 95% confidence interval (CI), 0.09–0.76]. The OR for the gene–environment interaction between heavy drinking and the 677TT genotype in the case-only design was 0.31 (95% CI, 0.10–0.94), indicating risk with heavy drinking to be 69% decreased in individuals harboring the 677TT genotype. We failed to find any significant interaction between either of the polymorphisms and smoking.

Abbreviations: ACCH, Aichi Cancer Center Hospital; CI, confidence interval; HWE, Hardy–Weinberg equilibrium; HERPACC, hospital-based epidemiologic research program at Aichi Cancer Center; MS, methionine synthase; MTHFR, methylenetetrahydrofolate reductase; OR, odds ratio; PYs, pack-years; PCR, polymerase chain reaction; SAdoMet, S-adenosylmethionine; SQFFQ, semi-quantitative food frequency questionnaire


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Folate deficiency caused by low consumption of vegetables and fruit has been recognized as a risk factor for esophageal cancer (13), this nutrient taking part in two biological pathways which influence neoplastic development. One is the synthesis of S-adenosylmethionine (SAdoMet), the universal methyl donor for biological methylation reactions, including DNA methylation, in which 5-methyltetrahydrofolate serves both as a cofactor and substrate. Thus, 5-methyltetrahydrofolate regenerates methionine from homocysteine which is further converted to SAdoMet. The other pathway is purine/thymidine synthesis, which is important for DNA synthesis and integrity, and requires 5,10-methylene-tetrahydrofolate as a coenzyme. Alteration in DNA methylation and disruption of DNA integrity and DNA repair are believed to enhance carcinogenesis by altering the expression of critical tumor suppressor genes and proto-oncogenes (4). Previous studies have shown that insufficient folate intake may increase cancer risk in sites like the esophagus (13).

Methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, catalyzes the reduction of 5,10-methylene-tetrahydrofolate to 5-methyltetrahydrofolate (5), while methionine synthase (MS), also plays an important role by catalyzing the transfer of a methyl group from 5-methyltetrahydrofolate to homocysteine, producing methionine and tetrahydrofolate (6). The genes encoding for MTHFR (MTHFR) and MS (MTR) both display functional polymorphisms. A substitution of C to T at nucleotide 677 in MTHFR results in an alanine to valine substitution, which alters enzyme activity (7). Thus, individuals with the 677TT genotype have ~30% the MTHFR enzyme activity of those with the 677CC genotype, whereas heterozygotes (677CT) have ~65%, as assessed in vitro (5). A substitution of A to G at nucleotide 2756 of MTR changes aspartic acid to glycine at codon 919 (8). Although a direct functional impact of this polymorphism has not been established, there is some evidence of an association with low homocysteine (911) and high serum folate (10). Several studies have indicated a substantial impact of these polymorphisms, and especially MTHFR C677T, on several types of cancer including colorectal cancer (12,13), acute lymphocytic leukemia (14) and malignant lymphoma (15,16); however, the situation regarding esophageal cancer is equivocal (1719).

To clarify the impact of folate intake, MTHFR C677T and MTR A2756G polymorphisms on esophageal cancer risk, and further to explore gene–environment interactions with drinking and smoking, we conducted the present case–control study.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Subjects
The cases were 165 patients who were histologically diagnosed as having esophageal cancers (159 squamous cell carcinomas and 6 adenocarcinomas) between January 2001 and August 2004 at Aichi Cancer Center Hospital (ACCH). The controls were first-visit outpatients who visited ACCH during the same period and were confirmed to have no cancer and also no prior history of cancer. They were randomly selected and matched for age and sex to cases with a 1:3 case–control ratio (n = 495). All the subjects, aged 18–80 years, were recruited in the framework of the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC), as described elsewhere (16,20,21). Briefly, all first-visit outpatients are asked to fill out a questionnaire regarding their lifestyle as well as to provide 7 ml of blood. Approximately 95% of eligible subjects complete the questionnaire and 60% provide blood samples. Our previous study showed that the lifestyle patterns of first-visit outpatients are accordant with those in the general population randomly selected from the Nagoya City electoral roll (22).

Genotyping of MTHFR and MTR
DNA of each subject was extracted from the buffy coat fraction with BioRobot EZ1 and an EZ1 DNA Blood 350 µl Kit (Qiagen K.K., Tokyo, Japan). The genotyping method was described in our previous report (16). Briefly, for the MTHFR polymorphism, extracted DNA was amplified with the forward primer 5'-TGA AGG AGA AGG TGT CTG CGG GA-3' and the reverse primer 5'-AGG ACG GTG CGG TGA GAG TG-3'. The polymerase chain reaction (PCR) 198 bp product was digested with HinfI (Boehringer Mannheim, Germany) and visualized after electrophoresis. For the MTR A2756G polymorphism, DNA was amplified with the forward primer 5'-TGT TCC AGA CAG TTA GAT GAA AAT C-3' and the reverse primer 5'-GAT CCA AAG CCT TTT ACA CTC CTC-3' and PCR products were digested with HaeIII (Boehringer Mannheim). Two controls failed to be amplified for MTHFR polymorphisms.

Assessment of folate intake
Assessment of folate intake was according to a semi-quantitative food frequency questionnaire (SQFFQ), which included 47 foods/food groups. The methods for developing the SQFFQ and computing the nutrient intake have been described elsewhere (2325). Briefly, folate intake was computed by multiplying the food intake (in grams) and the folate content (per gram) of food as listed in the Standard Tables of Food Composition and the Follow-up of the Standard Tables of Food Composition (2628), and then the sum of all folate intake from various foods/food groups was calculated as the total folate intake.

Statistical analysis
Statistical analyses were performed using Stata version 8 (Stata, College Station, TX). Conditional logistic regression was employed to calculate odds ratios (ORs) and their 95% confidence intervals (CIs). Alcohol exposure was categorized into three levels, non-drinker (never drinker), moderate drinker and heavy drinker. Heavy drinkers were defined as those drinking alcoholic beverages 5 days or more per week with an amount of 50 g or more ethanol on each occasion while moderate drinkers was defined as drinkers consuming less frequently and/or lower amounts. Smoking status was also divided into three categories considering cumulative exposure to tobacco: non-smokers (never smokers), smokers with pack-years (PYs) ≤40 (moderate smokers) and smokers with PYs >40 (heavy smokers). We combined the non-drinkers with moderate drinkers and non-smokers with those with a smoking dose <40 PYs for estimation of ORs (95% CI) for MTHFR, MTR and folate intake according to alcohol drinking and smoking, since the numbers of non-smokers and non-drinkers were limited among cases. Daily folate consumption of each person was adjusted for total energy intake based upon an established method (29). Gene–environment interactions were evaluated with case–control and case-only designs as described elsewhere (30). The ORs for interaction in the case–control study were exponential interaction terms in the conditional logistic regression model. Accordance with Hardy–Weinberg equilibrium (HWE) was checked for controls with the {chi}2-test and the exact P value was used to assess any discrepancies between genotype and allele frequencies.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 165 esophageal cases, with an average age of 61.4 years and 495 controls that matched with cases with reference to sex and age were included in the present study. Males accounted for 89.7% of the studied subjects. Heavy drinkers comprised 57% of the cases and this was significantly higher than for the controls, at 16.4%. Smoking habits also differed to a large extent between cases and controls, with 64.2% and only 33.3% current smokers, respectively. The mean adjusted daily folate consumption was 378.4 µg/day in cases and 393.5 µg/day in controls (Table I).


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Table I. Characteristics of cases and controls

 
Table II summarizes data for MTHFR and MTR genotype frequencies and folate intake with reference to esophageal cancer risk. The frequencies of CC, CT and TT (MTHFR C677T) were 37.7, 46 and 16.2% among controls and 38.2, 49.7 and 12.1% among cases, respectively. The genotype frequency was in accordance with the HWE in controls (P = 0.45). Individuals harboring the 677TT genotype showed a non-significantly decreased risk of esophageal cancer. The OR for the TT type was 0.66 (95% CI, 0.35–1.25) after adjusting for alcohol, smoking and folate intake. The genotype frequencies for MTR were 65.2% for AA, 31.8% for AG and 3.0% for GG among the controls, which was also in accordance with the HWE (P = 0.56). The GG type was very rare both among cases and controls and was associated only with a slightly increased risk of esophageal cancer, without statistical significance (OR = 1.33, 95% CI, 0.45–3.95). Table III summarizes the ORs for MTHFR and MTR gene polymorphisms and folate intake, according to the drinking and smoking status and cancer risk. Increase in the number of T alleles of MTHFR was associated with a significantly decreased risk in heavy drinkers and the same tendency was also found in heavy smokers, although non-significant in this case. The GG type of MTR was also linked to increased risk among heavy drinkers and heavy smokers, but this was not statistically significant. No marked variation in folate intake was observed according to drinking and smoking status.


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Table II. MTHFR, MTR genotype frequencies, folate intake and ORs for esophageal cancer

 

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Table III. ORsa,b (95% CI) for MTHFR, MTR and folate intake according to alcohol drinking and smoking

 
Table IV shows data for the combination of MTHFR gene polymorphisms and folate intake on esophageal cancer risk. Among the low folate intake group, risk did not differ across the three genotypes. The 677TT genotype showed a decreased risk of esophageal cancer only in the high folate intake group; however, the interaction between folate consumption and the MTHFR genotype was not significant. Impacts of heavy drinking or heavy smoking in combination with the MTHFR genotype are indicated in Tables V and VI. The risk was found to be consistently increased among heavy drinkers; however, the 677TT genotype showed a reduced risk relative to other genotypes. In contrast, risk differences were not marked in non-heavy drinkers. Significant interaction between heavy drinking and 677TT genotype for esophageal cancer risk (Table V) was found with both case-only (OR = 0.31, 95% CI, 0.10–0.94) and case–control (OR = 0.18, 95% CI, 0.05–0.63) designs. No significant interactions were found between smoking and MTHFR genotypes (Table VI).


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Table IV. Impact of low-folate intake in combination with the MTHFR genotype

 

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Table V. Impact of heavy drinking in combination with the MTHFR genotype

 

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Table VI. Impact of heavy smoking in combination with the MTHFR genotype

 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In this study, we found (i) high folate consumption and the MTHFR 677TT genotype to be associated with a non-significant decrease in the risk of esophageal cancer; (ii) a significant gene–environment interaction between MTHFR polymorphism and alcohol drinking, the 677TT genotype apparently reducing the esophageal cancer risk attributable to alcohol drinking; (iii) no significant interaction of either polymorphism with smoking.

Earlier epidemiological studies provided evidence that folate deficiency caused by low consumption of vegetables and fruit may be correlated with an increased risk of esophageal cancer (13). Our present results are in line with these findings although significance was not attained. Thus it is biologically plausible that genetic polymorphisms of enzymes involved in folate metabolism might have an impact on neoplasia in the esophagus.

To the best of our knowledge, there have been four studies hitherto performed examining the two polymorphisms on which we focused in this study: three in a high-risk area in China (1719) and one in Germany (19). The Chinese studies showed the MTHFR 677T allele to increase esophageal cancer risk (1719), while no risk change was observed among Caucasians in Germany (19). Our result for MTHFR genotype alone showed a tendency for lowered risk in individuals harboring the 677TT genotype. Regional differences in folate consumption among populations may be a possible explanation for this inconsistency in direction of impact of the T allele, as Song et al. have discussed (17). In brief, studies on colorectal cancer have suggested that cancer risk associated with MTHFR polymorphisms depends on the level of folate intake (13,31). Therefore, one could hypothesize a gene–nutrient interaction between folate consumption and the direction of impact of the MTHFR 677T allele. Based on this hypothesis, when folate intake is sufficient, individuals with the MTHFR CT or TT genotypes may have a decreased risk of cancer, since decrease in MTHFR activity associated with the 677TT polymorphism might lead to an elevation in 5,10-methylene-tetrahydrofolate, facilitating DNA synthesis, while adequate provision of methyl donors could still be ensured. In contrast, in the presence of low folate intake, both impaired DNA methylation and DNA synthesis/repair may become the primary mechanisms of carcinogenesis. Although non-significant, our result is consistent with this hypothesis, indicating decreased esophageal cancer risk attributed to the TT genotype among the high folate group but a slightly increased risk among the low folate group (Table IV). The fact that average folate intake in our control group was 393.5 µg/day, as compared with 294 µg/day in urban Chinese in Shanghai (32), may support this explanation. The folate intake may be much lower in high-risk esophageal cancer areas of China and Stolzenberg-Solomon et al. (18) found 90% of a high-risk population to have a low folate status. Therefore, the MTHFR 677TT genotype may decrease the esophageal cancer risk among Japanese, a folate intake sufficient group, as observed for other cancers in developed countries (1216,33,34).

The significant finding in this study was the interaction between the MTHFR TT genotype and heavy alcohol drinking, with both case-only and case–control designs. Previous studies have not examined this issue in detail (1719) and to our knowledge, this is the first study to show a significant interaction between the MTHFR TT genotype and alcohol drinking. Heavy drinking is recognized as a major risk factor for esophageal cancer (3537) and alcohol is considered to induce DNA damage and resultant modification of nucleotides (38). Therefore, it is biologically plausible that those harboring the 677TT genotype, who are expected to have high 5,10-methylene-tetrahydrofolate concentrations, would have lower esophageal cancer risk when exposed to high amounts of alcohol. Research on hepatocellular carcinoma cases and controls also found relative protection against cancer conveyed by the T allele among alcoholics (39).

No studies of MTR polymorphisms and esophageal cancer risk have hitherto been reported and previous findings for colorectal cancer (33,4043) and lymphoma (15,16,44) risk were inconsistent. The MTR GG type was rare in the present study, in line with earlier findings (15,16,42).

Potential limitations of the present study should be considered. One methodological issue is selection of the base population for controls. We applied non-cancer patients at the ACCH for this purpose because it is reasonable to assume our cases arose within this population base. A notable point of our control population is its similarity to the general population in terms of exposures of interest, here smoking and drinking (22). Similarity in the genotype distribution for the MTHFR C677T polymorphism between our controls and the general population has also been confirmed (45). The medical background of controls is another potential source of bias; however, our previous study focused on females demonstrated a limited impact. More than 66% of non-cancer outpatients at ACCH do not have any specific medical condition. The remaining 34% have specific diseases, like benign tumors and/or non-neoplastic polyps (13.1%), mastitis (7.5%), digestive disease (4.1%) or benign gynecological disease (4.1%) (46). As for men, the circumstance is similar. This situation is very different from that in other developed countries, where people visit local general clinics first, and are then referred to hospitals which function as secondary and/or specific facilities for further medical treatment. We therefore conclude that it is feasible to use non-cancer outpatients as referents in HERPACC type epidemiological studies. In addition, the present study was free of response information bias to the questionnaire because all data were collected prior to diagnoses.

In conclusion, our case–control study suggested a significant gene–environment interaction between alcohol drinking and the MTHFR 677TT genotype. Thus the esophageal cancer risk due to alcohol was decreased markedly by harboring the 677TT genotype.


    Acknowledgments
 
The first author was the recipient of a Japan–China Special Sasakawa Medical Fellowship during the performance of this research. The study was supported in part by a Grant-in-Aid for Scientific Research on Cancer Epidemiology in a Special Priority Area (c) (Grant No. 12670383) from the Ministry of Education, Science, Sports, Culture and Technology of Japan. The authors are grateful to Achiwa, Sato and Watanabe for their technical help for laboratory assays. The authors are also grateful to Fujikura, Fukaya, Kamori, Tomita, Hattori, Shimada, Sato, Yamauchi and Yoshida for their help in interviewing and data collection/cleaning.

Conflict of Interest Statement: None declared.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

  1. Yang,C.S. (2000) Vitamin nutrition and gastroesophageal cancer. J. Nutr., 130, 338S–339S.[ISI][Medline]
  2. Mayne,S.T., Risch,H.A., Dubrow,R. et al. (2001) Nutrient intake and risk of subtypes of esophageal and gastric cancer. Cancer Epidemiol. Biomarkers Prev., 10, 1055–1062.[Abstract/Free Full Text]
  3. Chen,H., Tucker,K.L., Graubard,B.I., Heineman,E.F., Markin,R.S., Potischman,N.A., Russell,R.M., Weisenburger,D.D. and Ward,M.H. (2002) Nutrient intakes and adenocarcinoma of the esophagus and distal stomach. Nutr. Cancer, 42, 33–40.[CrossRef][ISI][Medline]
  4. Choi,S.W. and Mason,J.B. (2000) Folate and carcinogenesis: an integrated scheme. J. Nutr., 130, 129–132.[Abstract/Free Full Text]
  5. Bailey,L.B. and Gregory,J.F.,III (1999) Polymorphisms of methylenetetrahydrofolate reductase and other enzymes: metabolic significance, risks and impact on folate requirement. J. Nutr., 129, 919–922.[Abstract/Free Full Text]
  6. Banerjee,R.V. and Matthews,R.G. (1990) Cobalamin-dependent methionine synthase. FASEB J., 4, 1450–1459.[Abstract/Free Full Text]
  7. Goyette,P., Sumner,J.S., Milos,R., Duncan,A.M., Rosenblatt,D.S., Matthews,R.G. and Rozen,R. (1994) Human methylenetetrahydrofolate reductase: isolation of cDNA mapping and mutation identification. Nat. Genet., 7, 551.
  8. Leclerc,D., Odievre,M., Wu,Q., Wilson,A., Huizenga,J.J., Rozen,R., Scherer,S.W. and Gravel,R.A. (1999) Molecular cloning, expression and physical mapping of the human methionine synthase reductase gene. Gene, 240, 75–88.[CrossRef][ISI][Medline]
  9. Dekou,V., Gudnason,V., Hawe,E., Miller,G.J., Stansbie,D. and Humphries,S.E. (2001) Gene–environment and gene–gene interaction in the determination of plasma homocysteine levels in healthy middle-aged men. Thromb. Haemost., 85, 67–74.[ISI][Medline]
  10. Chen,J., Stampfer,M.J., Ma,J., Selhub,J., Malinow,M.R., Hennekens,C.H. and Hunter,D.J. (2001) Influence of a methionine synthase (D919G) polymorphism on plasma homocysteine and folate levels and relation to risk of myocardial infarction. Atherosclerosis, 154, 667–672.[CrossRef][ISI][Medline]
  11. Harmon,D.L., Shields,D.C., Woodside,J.V., McMaster,D., Yarnell,J.W., Young,I.S., Peng,K., Shane,B., Evans,A.E. and Whitehead,A.S. (1999) Methionine synthase D919G polymorphism is a significant but modest determinant of circulating homocysteine concentrations. Genet. Epidemiol., 17, 298–309.[CrossRef][ISI][Medline]
  12. Slattery,M.L., Potter,J.D., Samowitz,W., Schaffer,D. and Leppert,M. (1999) Methylenetetrahydrofolate reductase, diet, and risk of colon cancer. Cancer Epidemiol. Biomarkers Prev., 8, 513–518.[Abstract/Free Full Text]
  13. Ma,J., Stampfer,M.J., Giovannucci,E., Artigas,C., Hunter,D.J., Fuchs,C., Willett,W.C., Selhub,J., Hennekens,C.H. and Rozen,R. (1997) Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res., 57, 1098–1102.[Abstract]
  14. Skibola,C.F., Smith,M.T., Kane,E., Roman,E., Rollinson,S., Cartwright,R.A. and Morgan,G. (1999) Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc. Natl Acad. Sci. USA, 96, 12810–12815.[Abstract/Free Full Text]
  15. Matsuo,K., Suzuki,R., Hamajima,N. et al. (2001) Association between polymorphisms of folate- and methionine-metabolizing enzymes and susceptibility to malignant lymphoma. Blood, 97, 3205–3209.[Abstract/Free Full Text]
  16. Matsuo,K., Hamajima,N., Suzuki,R. et al. (2004) Methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms and reduced risk of malignant lymphoma. Am. J. Hematol., 77, 351–357.[CrossRef][ISI][Medline]
  17. Song,C., Xing,D., Tan,W., Wei,Q. and Lin,D. (2001) Methylenetetrahydrofolate reductase polymorphisms increase risk of esophageal squamous cell carcinoma in a Chinese population. Cancer Res., 61, 3272–3275.[Abstract/Free Full Text]
  18. Stolzenberg-Solomon,R.Z., Qiao,Y.L., Abnet,C.C., Ratnasinghe,D.L., Dawsey,S.M., Dong,Z.W., Taylor,P.R. and Mark,S.D. (2003) Esophageal and gastric cardia cancer risk and folate- and vitamin B(12)-related polymorphisms in Linxian, China. Cancer Epidemiol. Biomarkers Prev., 12, 1222–1226.[Abstract/Free Full Text]
  19. Zhang,J., Zotz,R.B., Li,Y. et al. (2004) Methylenetetrahydrofolate reductase C677T polymorphism and predisposition towards esophageal squamous cell carcinoma in a German Caucasian and a northern Chinese population. J. Cancer Res. Clin. Oncol., 130, 574–580.[ISI][Medline]
  20. Hamajima,N., Matsuo,K., Saito,T., Hirose,K., Inoue,M., Takezaki,T., Kuroishi,T. and Tajima,K. (2001) Gene–environment interactions and polymorphism studies of cancer risk in the hospital-based epidemiologic research program at Aichi Cancer Center II (HERPACC-II). Asian Pac. J. Cancer Prev., 2, 99–107.[Medline]
  21. Yang,C.X., Takezaki,T., Hirose,K., Inoue,M., Huang,X.E. and Tajima,K. (2003) Fish consumption and colorectal cancer: a case-reference study in Japan. Eur. J. Cancer Prev., 12, 109–115.[CrossRef][ISI][Medline]
  22. Inoue,M., Tajima,K., Hirose,K., Hamajima,N., Takezaki,T., Kuroishi,T. and Tominaga,S. (1997) Epidemiological features of first-visit outpatients in Japan: comparison with general population and variation by sex, age, and season. J. Clin. Epidemiol., 50, 69–77.[CrossRef][ISI][Medline]
  23. Tokudome,S., Ikeda,M., Tokudome,Y., Imaeda,N., Kitagawa,I. and Fujiwara,N. (1998) Development of data-based semi-quantitative food frequency questionnaire for dietary studies in middle-aged Japanese. Jpn. J. Clin. Oncol., 28, 679–687.[Abstract/Free Full Text]
  24. Tokudome,S., Goto,C., Imaeda,N., Tokudome,Y., Ikeda,M. and Maki,S. (2004) Development of a data-based short food frequency questionnaire for assessing nutrient intake by middle-aged Japanese. Asian Pac. J. Cancer Prev., 5, 40–43.[Medline]
  25. Tokudome,Y., Goto,C., Imaeda,N., Hasegawa,T., Kato,R., Hirose,K., Tajima,K. and Tokudome,S. (2005) Relative validity of a short food frequency questionnaire for assessing nutrient intakes versus 3-day weighed diet records in middle-aged Japanese. J Epidemiol., in press.
  26. Resources Council,S.a.T.A., Japan (1982) Standard Tables of Food Composition in Japan, 4th edn. Ministry of Finance (in Japanese), Tokyo.
  27. Resources Council,S.a.T.A., Japan (1992) Follow-up of Standard Tables of Food Composition in Japan. Ishiyaku Shuppan (in Japanese), Tokyo.
  28. Resources Council,S.a.T.A., Japan (1993) Standard Tables of Food Composition in Japan, 5th edn. Ministry of Finance (in Japanese), Tokyo.
  29. Willett,W. and Stampfer,M.J. (1986) Total energy intake: implications for epidemiologic analyses. Am. J. Epidemiol., 124, 17–27.[Abstract]
  30. Hamajima,N., Yuasa,H., Matsuo,K. and Kurobe,Y. (1999) Detection of gene–environment interaction by case-only studies. Jpn. J. Clin. Oncol., 29, 490–493.[Abstract/Free Full Text]
  31. Chen,J., Giovannucci,E., Kelsey,K., Rimm,E.B., Stampfer,M.J., Colditz,G.A., Spiegelman,D., Willett,W.C. and Hunter,D.J. (1996) A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer. Cancer Res., 56, 4862–4864.[Abstract]
  32. Shrubsole,M.J., Jin,F., Dai,Q., Shu,X.O., Potter,J.D., Hebert,J.R., Gao,Y.T. and Zheng,W. (2001) Dietary folate intake and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Res., 61, 7136–7141.[Abstract/Free Full Text]
  33. Le Marchand,L., Donlon,T., Hankin,J.H., Kolonel,L.N., Wilkens,L.R. and Seifried,A. (2002) B-vitamin intake, metabolic genes, and colorectal cancer risk (United States). Cancer Causes Control, 13, 239–248.[CrossRef][ISI][Medline]
  34. Giovannucci,E., Chen,J., Smith-Warner,S.A., Rimm,E.B., Fuchs,C.S., Palomeque,C., Willett,W.C. and Hunter,D.J. (2003) Methylenetetrahydrofolate reductase, alcohol dehydrogenase, diet, and risk of colorectal adenomas. Cancer Epidemiol. Biomarkers Prev., 12, 970–979.[Abstract/Free Full Text]
  35. Takezaki,T., Shinoda,M., Hatooka,S. et al. (2000) Subsite-specific risk factors for hypopharyngeal and esophageal cancer (Japan). Cancer Causes Control, 11, 597–608.[CrossRef][ISI][Medline]
  36. Hanaoka,T., Tsugane,S., Ando,N. et al. (1994) Alcohol consumption and risk of esophageal cancer in Japan: a case–control study in seven hospitals. Jpn. J. Clin. Oncol., 24, 241–246.[Abstract]
  37. Matsuo,K., Hamajima,N., Shinoda,M., Hatooka,S., Inoue,M., Takezaki,T. and Tajima,K. (2001) Gene–environment interaction between an aldehyde dehydrogenase-2 (ALDH2) polymorphism and alcohol consumption for the risk of esophageal cancer. Carcinogenesis, 22, 913–916.[Abstract/Free Full Text]
  38. Wu,D. and Cederbaum,A.I. (2003) Alcohol, oxidative stress, and free radical damage. Alcohol Res. Health, 27, 277–284.[ISI][Medline]
  39. Saffroy,R., Pham,P., Chiappini,F., Gross-Goupil,M., Castera,L., Azoulay,D., Barrier,A., Samuel,D., Debuire,B. and Lemoine,A. (2004) The MTHFR 677C > T polymorphism is associated with an increased risk of hepatocellular carcinoma in patients with alcoholic cirrhosis. Carcinogenesis, 25, 1443–1448.[Abstract/Free Full Text]
  40. Ulvik,A., Vollset,S.E., Hansen,S., Gislefoss,R., Jellum,E. and Ueland,P.M. (2004) Colorectal cancer and the methylenetetrahydrofolate reductase 677C -> T and methionine synthase 2756A -> G polymorphisms: a study of 2,168 case–control pairs from the JANUS cohort. Cancer Epidemiol. Biomarkers Prev., 13, 2175–2180.[Abstract/Free Full Text]
  41. Goode,E.L., Potter,J.D., Bigler,J. and Ulrich,C.M. (2004) Methionine synthase D919G polymorphism, folate metabolism, and colorectal adenoma risk. Cancer Epidemiol. Biomarkers Prev., 13, 157–162.[Abstract/Free Full Text]
  42. Matsuo,K., Hamajima,N., Hirai,T., Kato,T., Inoue,M., Takezaki,T. and Tajima,K. (2002) Methionine synthase reductase gene A66G polymorphism is associated with risk of colorectal cancer. Asian Pac. J. Cancer Prev., 3, 353–359.[Medline]
  43. Ma,J., Stampfer,M.J., Christensen,B. et al. (1999) A polymorphism of the methionine synthase gene: association with plasma folate, vitamin B12, homocyst(e)ine, and colorectal cancer risk. Cancer Epidemiol. Biomarkers Prev., 8, 825–829.[Abstract/Free Full Text]
  44. Skibola,C.F., Forrest,M.S., Coppede,F., Agana,L., Hubbard,A., Smith,M.T., Bracci,P.M. and Holly,E.A. (2004) Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma. Blood, 104, 2155–2162.[Abstract/Free Full Text]
  45. Yoshimura,K., Hanaoka,T., Ohnami,S., Kohno,T., Liu,Y., Yoshida,T., Sakamoto,H. and Tsugane,S. (2003) Allele frequencies of single nucleotide polymorphisms (SNPs) in 40 candidate genes for gene–environment studies on cancer: data from population-based Japanese random samples. J. Hum. Genet., 48, 654–658.[CrossRef][ISI][Medline]
  46. Hamajima,N., Hirose,K., Inoue,M., Takezaki,T., Kuroishi,T. and Tajima,K. (1995) Age-specific risk factors of breast cancer estimated by a case–control study in Japan. J. Epidemiol., 5, 99–105.
Received January 16, 2005; revised March 4, 2005; accepted March 16, 2005.





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