One-carbon metabolism related gene polymorphisms interact with alcohol drinking to influence the risk of colorectal cancer in Japan

Keitaro Matsuo 1, *, Hidemi Ito 1, Kenji Wakai 1, Kaoru Hirose 1, Toshiko Saito 1, Takeshi Suzuki 1, 4, Tomoyuki Kato 2, Takashi Hirai 2, Yukihide Kanemitsu 2, Hiroshi Hamajima 3 and Kazuo Tajima 1

1 Division of Epidemiology and Prevention, 2 Department of Gastroenterological Surgery, 3 Department of Clinical Laboratory, Aichi Cancer Center, Chikusa-ku, Nagoya 464-8681, Japan and 4 Department of Internal Medicine and Molecular Science, Nagoya City University Graduate School of Medical Science, Nagoya Aichi, Nagoya 467-8601, Japan

* To whom correspondence should be addressed. Fax: +81 52 763 5233; Email: kmatsuo{at}aichi-cc.jp


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
One-carbon metabolism, in which folate plays an essential role, is involved in DNA methylation and synthesis, and is suspected of impacting on colorectal carcinogenesis. Alcohol is well recognized as a risk factor for colorectal cancer (CRC) and interactions with one-carbon metabolism have also been suggested. Therefore, functional polymorphisms in genes encoding members of this pathway, MTHFR C677T and A1298C (genes for methylenetetrahydrofolate reductase), MTR A2756G (gene for methionine synthase) and TS (gene for thymidylate synthase) tandem repeats polymorphisms, have attracted attention. We conducted a matched case–control study with 257 incident CRC cases and 771 non-cancer controls at the Aichi Cancer Center to clarify associations among folate intake and four polymorphisms with reference to CRC risk. Gene–environment interaction between polymorphisms, drinking and folate consumption was also evaluated. None of the polymorphisms showed any significant impact on CRC risk by genotype alone, but when combined with alcohol consumption the MTHFR 677CC type showed a significantly reduced risk (odds ratio (OR) = 0.45, 95% confidence interval (CI): 0.23–0.86) (P = 0.01). MTR GG showed increased risk only among drinkers (OR = 3.35, 1.40–8.05) (P = 0.047). TS polymorphism did not show statistical significance by genotype alone, while interaction with drinking was significant (P = 0.028). The association was not changed even after stratification by daily folate consumption and drinking habit. In conclusion, we found consistently significant interactions between one-carbon metabolism-related polymorphisms and alcohol drinking.

Abbreviations: ACCH, Aichi Cancer Center Hospital; BMI, body-mass index; CRC, colorectal cancer; FVO, first visit outpatients; HWE, Hardy–Weinberg equilibrium; HERPACC, Hospital-based Epidemiologic Research Program at Aichi Cancer Center; MS, methionine synthase; MTHFR, methylenetetrahydrofolate reductase; PY, pack-year; PCR, polymerase chain reaction; PCR-RFLP, PCR-restriction-fragment-length polymorphism; SQFFQ, semi-quantitative food frequency questionnaire; TS, thymidylate synthase; 2R, two repeats allele; VNTR, variable number of tandem repeat


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Recent understanding of one-carbon metabolism, in which the micronutrients, such as folate, methionine and vitamin B12, play important roles, has suggested an influence on carcinogenesis (13). There are two main branches of the pathway: one consists of reactions involving thymidine synthesis, and the other is responsible for synthesis of methionine and S-adenosylmethionine required for methylation reactions. Therefore, disturbance in this pathway may lead to aberrant DNA synthesis and DNA methylation. Epidemiological evidence that folate intake is associated with reduced risk of several types of cancer strongly supports the biological plausibility of one-carbon metabolism being related to carcinogenesis (46).

Polymorphisms in the genes for methylenetetrahydrofolate reductase (MTHFR) (MTHFR C677T and A1298C) (7,8), methionine synthase (MS) (MTR A2756G)(9,10) and thymidylate synthase (TS) (TS 28-bp variable number of tandem repeat (VNTR) in the promoter region) (11,12) are known to have functional relevance and many epidemiological studies have provided evidence of associations regarding several types of malignancies (1317). Colorectal cancer (CRC) is one of the cancers most extensively studied in the last decade (13,15,1831).

Alcohol consumption is recognized as another risk factor of CRC, with an antagonistic effect on folate (32). Earlier studies on MTHFR C677T polymorphism reported that protective effect by the TT genotype was evident with the subjects who seldom drink, but not with those who consume drinks (13,18). However, subsequent results were not necessarily in accordance (15,23,26,28,29,31), showing a stronger interaction with moderate than high level of drinking. Information is limited regarding the MTHFR A1298C, MTR A2756G and TS VNTR polymorphisms, and the present case–control study was therefore conducted to clarify their impact on CRC risk in combination with alcohol drinking.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Subjects
The cases were 257 patients who were histologically diagnosed as having CRCs (123 colon cancers, 131 rectal cancers and 3 CRCs) between January 2001 and August 2004 at Aichi Cancer Center Hospital (ACCH) and not having any earlier history of cancer. Controls were first visit outpatients (FVO) who visited ACCH during the same period as cases and were confirmed to have no cancers and no prior history of cancers. Controls were randomly selected and matched for age and sex strata to cases with a 1:3 case:control ratio (n = 771). All of the cases and controls were selected from the database of the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC) as described previously (3335).

ACCH plays a role as a referral center around Aichi Prefecture. The FVO who are referred from other clinics and primary screening centers comprise 32 and 19% of all the FVO, respectively. Subjects can visit ACCH by patients' or families' will to utilize ACCH as a screening center. The latter subjects comprise 48% of FVO. Of all the FVOs, ~30% are pathologically diagnosed as having cancer and the rest of them are proved to have no detectable cancer. Based upon this background of ACCH, the HERPACC system has been constructed since 1988. In HERPACC, all the FVO from all the departments, aged 18–80 years, are asked to complete a questionnaire and to provide blood samples. In all ~95% FVOs completed the questionnaire and 60% of them provided blood samples, therefore, the subjects in this study were selected from within this 60% population who enrolled in HERPACC. Under the assumption that the non-cancer subjects in this population are source population of the future cases at ACCH, which would support internal validity of the study, we used the non-cancer subjects in HERRPACC database as the control source. Our previous study showed lifestyle patterns of FVOs to be accordant with those in the general population randomly selected from the Nagoya City electoral roll, partly supporting external validity of the results (36).

Genotyping of MTHFR, MTR and TS
DNA of each subject was extracted from the buffy coat fraction using BioRobot EZ1 and a EZ1 DNA Blood 350 µl Kit (Qiagen, Tokyo, Japan). The genotyping method was described in our previous reports with polymerase chain reaction (PCR) or PCR-restriction-fragment-length polymorphism (PCR-RFLP) methods (17,34). Briefly, for the MTHFR C677T and A1298C and MTR A2576G polymorphisms, extracted DNA was amplified with 5'-TGA AGG AGA AGG TGT CTG CGG GA-3' and 5'-AGG ACG GTG CGG TGA GAG TG-3', 5'-ATG TGG GGG GAG GAG CTG AC-3' and 5'- GTC TCC CAA CTT ACC CTT CTC CC-3', and 5'-TGT TCC AGA CAG TTA GAT GAAAAT C-3' and 5'-GAT CCAAAG CCT TTT ACA CTC CTC-3', respectively, followed by digestion with HinfI, MboII and HaeIII (Boehringer Mannheim, Germany). The TS VNTR polymorphism was defined by PCR using 5'- CGT GGC TCC TGC GTT TCC-3' and 5'-GAG CCG GCC ACA GGC AT-3' primers.

In our laboratory, quality of genotyping was routinely assessed statistically by using the Hardy–Weinberg test. When allelic distributions for controls departed from the Hardy–Weinberg frequency, genotyping was assessed using another method. Identification of the genotype was accomplished with a double-blind check, and the results were loaded into the computer by two researchers independently.

Assessment of folate intake and alcohol 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 were described previously (3739). Briefly, folate intake was computed by multiplying the food intake (in grams) and the folate content (per gram) of the food as listed in the Standard Tables of Food Composition and the Follow-up of the Standard Tables of Food Composition (4042), and then the sum of all folate intake from various foods/food groups was calculated as the total folate intake. In the validity test comparing SQFFQ and in 3-day weighed dietary records among 222 healthy volunteers aged 30–70 years, de-attenuated, log-transformed and energy adjusted Pearson's correlation coefficients were 0.36 [95% confidence interval (CI): 0.12–0.58] for males and 0.38 for females (95% CI: 0.25–0.62) (39).

Consumption of each type of beverage (Japanese sake, beer, shochu, whiskey and wine) was determined by the average number of drinks per day, which was then converted into a Japanese sake (rice wine) equivalent. One drink equates to one ‘go’ (180 ml) of Japanese sake, which contains 25 g of ethanol, one large bottle (720 ml) of beer, two shots (57 ml) of whiskey and two and a half glasses of wine (200 ml). One drink of ‘Shochu’ (distilled spirit), which contains 25% ethanol, was rated as 108 ml. Total amount of alcohol consumption was estimated as the summarized amount of pure alcohol consumption (g/drink) of Japanese sake, beer, shochu, whiskey and wine among current and former regular drinkers.

Statistical analysis
Statistical analyses were performed using Stata version 8 (Stata, College Station, TX). A P-value <0.05 was applied for statistical significance, and adjustment for multiple comparisons was not considered because of the exploratory nature of the study. Conditional logistic regression was employed to calculate odds ratios (ORs) and their 95% CIs. Alcohol exposure was categorized into three levels, non-drinker, moderate drinker and heavy drinker. The last was defined as consuming alcoholic beverages 5 days or more per week with an amount of 50 g or more ethanol on each occasion, while moderate drinkers included all other drinkers. 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). Energy adjusted daily folate consumption was categorized into quartiles and the threshold for quartiles was defined by values for controls (311.1, 383.2 and 477.1 µg/day were the threshold in each level of quartile). Potential confounders considered in the multivariate analyses were age, sex, referral pattern to ACCH, body-mass index (BMI), hours of daily physical exercise and family history of CRC. Family history was defined as presence of the disease in a parent or sibling. Gene–environment interactions between alcohol drinking and genotypes in each polymorphism were evaluated under the multiplicative assumption. Products of scores for genotype (0, homozygous referent allele; 1, heterozygous referent allele; and 2, homozygous non-referent allele) and drinking status (0, non-drinker; and 1, drinker; or 0, non-drinker; 1, moderate drinker; and 2, heavy drinker) were included as interaction terms. Accordance with Hardy–Weinberg equilibrium (HWE) was checked for controls using 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
 
Table I shows baseline characteristics for the total of 257 colorectal cancer cases, with an average age of 58.8, and the 771 controls matched with cases with reference to sex and age. Males accounted for 63.0% of the studied subjects. Neither the drinking nor the smoking status significantly differed between the two groups. Energy adjusted daily folate consumption was slightly higher among controls, though this was not significant. BMI and physical exercise also did not differ. However, a family history of CRC was significantly more prevalent in the cases (P = 0.038). There was no difference between colon and rectal cancers.


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Table I. Characteristics of cases and controls

 
Table II shows genotype distributions for MTHFR, MTR and TS, and their ORs and 95% CIs for CRC. The genotype frequencies for all the polymorphisms were in accordance with the HWE in controls and allele frequencies were also quite accordant with those in earlier reports in Japan (43,44). The frequencies of CC, CT and TT (MTHFR C677T) were 37.5, 45.1 and 17.4% among controls and 41.4, 44.5 and 14.1% among cases, respectively. Although not significant, a trend for reduced risk was observed as the number of 677T alleles increased. The frequencies of AA, AC and CC of the MTHFR A1298C polymorphism were 62.5, 33.5 and 4.0% among controls and 63.4, 33.1 and 3.5% among cases, respectively. Similarly, ORs decreased as number of the 1298C alleles increased, again without significance, and with the combination of the two MTHFR polymorphisms. The genotype frequencies for MTR were 64.7% for AA, 32.0% for AG and 3.2% for GG among controls and 64.2% for AA, 30.4% for AG and 5.5% for GG among cases. Although the GG type was rare among both cases and controls, a slightly increased risk of CRC, without statistical significance, was observed. The genotype frequencies for TS VNTR were quite varied. Several carriers of five/six repeat alleles were observed both in cases and controls; however, two repeat (2R) and three repeat alleles were dominant. As the 2R allele is recognized as low expression of TS protein, we summarized the distribution as in Table II. The 2R2R genotype showed decreasing risk trend of CRC as compared with the non-2R homozygous, although not significant.


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Table II. MTHFR, MTR and TS genotype distributions, and ORs for CRC

 
Table III summarizes ORs for MTHFR, MTR and TS VNTR gene polymorphisms according to the drinking habit. The gene–environment interaction with drinking was significant for the MTHFR C677T genotype and for the combination of C677T and A1298C, while that for A1298C genotype did not achieve statistical significance. The ORs for the MTHFR 677CT and TT genotypes were 0.81 (95% CI: 0.54–1.21) and 0.45 (0.23–0.86), respectively, with a significant trend (P = 0.018). Although ORs for MTHFR A1298C genotypes were not significant, the combination of C677T and A1298C showed decreasing risk as the number of 677T or 1298C alleles increased among drinkers (P-trend = 0.029). Further stratification by the level of drinking indicated that the association was more evident in moderate drinkers than in heavy drinkers.


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Table III. Interaction between MTHFR, MTR and TS polymorphisms and drinking for CRC risk

 
Table III also summarizes data for the impact of MTR A2756G and TS VNTR polymorphisms. Gene–environment interaction with drinking for MTR and TS polymorphisms were both statistically significant (P = 0.047 and 0.027, respectively). The MTR GG genotype showed significantly increased risk of CRC with an OR of 3.35 (1.40–8.05) only among drinkers and the difference from non-drinkers was detected as a significant interaction (P = 0.047). Further stratification by the level of drinking showed consistent CRC risk elevation, with drinkers having the GG genotype. As for TS, a trend for decreased risk (P = 0.067) was observed with 2R carriers among non-drinkers, while increased risk trend among drinkers was observed.

The impact of each polymorphism with reference to daily folate consumption was examined. Neither clear association nor interaction was observed in the analysis treating quartile separately (data not shown). Therefore, we decided to analyze by dichotomizing the folate consumption, the lowest quartile and others as presented in Table IV. No statistically significant interactions were observed for any of the polymorphisms; however, the MTHFR C677T polymorphism showed a marginally significant impact among those consuming less folate (Quartile 1). Table V presents ORs for CRC according to combination of folate consumption and drinking. The MTR GG genotype was associated with a statistically significant increase in risk only among drinkers who were low consumers of folate (OR, 4.78; 95% CI: 1.67–13.7). A similar trend was observed with the TS 2R2R genotype. In accordance with Table III, the MTHFR C677T polymorphism demonstrated a trend for decrease among drinkers. Risk reduction was significant in drinkers with low folate consumption, but a similar non-significant trend was also observed with drinkers having high folate consumption.


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Table IV. Interaction between MTHFR, MTR and TS polymorphisms and folate for CRC risk

 

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Table V. Effect of folate consumption and alcohol drinking on MTHFR, MTR and TS polymorphisms

 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In this study, we found that (i) one-carbon metabolism-related polymorphisms consistently interact with alcohol drinking for the risk of CRC, while not showing a significant impact by themselves; (ii) interactions between alcohol and polymorphisms are more evident among moderate than among heavy drinkers; (iii) folate consumption might interact with MTHFR polymorphisms; and (iv) MTR and TS might have an impact with the coexistence of alcohol drinking and low folate consumption.

The alcohol metabolite, acetaldehyde, can cleave folate (45), and ethanol reaching the large bowel mucosa, where the concentration is equal to that in blood stream (46), is converted to acetaldehyde by intestinal microorganisms (47), thus leading to depletion of folate in the intestinal mucosa. This might further lead to disturbance in DNA synthesis and methylation and it is reasonable to consider that the functional variation in the genes for one-carbon metabolism interact with habitual drinking. Interactions between alcohol consumption and MTHFR C677T polymorphisms have in fact been already reported by many authors (13,15,18,23,26,2830), but to our knowledge this is the first study to demonstrate interactions between alcohol consumption and MTR A2756G and TS VNTR polymorphisms regarding the risk of CRC. Our findings provide further support for the hypothesis of links between one-carbon metabolism and alcohol influence on colorectal carcinogenesis.

It is of interest that the alcohol consumption level has a substantial impact with one-carbon related polymorphisms, greater effects being seen in this study with moderate drinkers. Earlier studies of the MTHFR C677T polymorphism in combination with alcohol consumption demonstrated protective effects of the 677TT genotype with low to moderate drinkers, as summarized in Table VI (13,15,18,23,26,2830). As categories for alcohol consumption differed in each study, further evaluation by meta-analysis of individual data applying unified consumption levels is needed for clarification. Regarding other polymorphisms, further accumulation of evidence is required.


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Table VI. Review of epidemiologic studies for CRC examining MTHFR C677T polymorphism in combination with alcohol drinking

 
Combination effects of folate consumption and alcohol drinking have attracted much attention, given the biologically plausible role of acetaldehyde, but not all epidemiological studies have supported combined effects (3). In the present case, we did not find a strong effect of folate overall. The estimation error of folate consumption by SQFFQ could be one possible explanation for the absence of association. As Japanese take folate from natural food items rather than folate containing multivitamin and/or folate fortified foods, the intake is basically covered by SQFFQ. However, as Taguchi et al. (48) suggested, the underestimation of folate consumption based upon commonly used food composition tables might bias the measurement of folate. Therefore, measurement by using SQFFQ could be considered as a potential limitation of our study and evaluations in other studies are required in this respect.

We here found an increased risk with those drinking alcohol and having the MTR GG genotype. Inconsistent observations regarding the direction of influence of the MTR GG genotype have been reported (21,26,27,31), and the association with folate consumption and alcohol is furthermore unclear. Further studies are required to clarify ethnic differences in the MTR A2756G polymorphism. Regarding the TS VNTR polymorphism, we did not find a significant effect only by genotype; however, a trend for increased risk was evident with the 2R2R genotype among drinkers with low folate consumption (Table V). Basically the 2R allele is recognized as a low expression allele and lowered function of TS might lead to disturbance in DNA synthesis (11,12). However, a completely opposite finding was reported for colorectal adenomas (48), so that further examination is warranted.

Potential limitations of the present study should be considered. In this study, actual folate levels were not measured. We could expect that measuring folate levels might have revealed significant interactions between folate, alcohol and genotypes on CRC risk that were not observed with folate intake in this study. One of the other methodological issues is the 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 to parameters of interest, smoking and drinking in this study (36). Similarity in the genotype distribution for the MTHFR C677T polymorphism between our controls and the general population has also been reported (44). Medical background of controls is another potential source of bias; however, our previous study focusing on females demonstrated a limited impact (50). With 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. Relatively small sample size of cases is a potential limitation of the study to explore multiple interactions, thus, careful interpretation is required.

In conclusion, our case–control study suggested consistently significant gene–environment interactions between alcohol drinking and MTHFR C677T, MTR A2756G and TS VNTR polymorphisms for CRC risk in the Japanese population.


    Acknowledgments
 
The authors are grateful to Ms Fujikura, Mss Fukaya, Kamori, Tomita, Hattori, Shimada, Sato, Yamauchi and Yoshida for their help with this study. This 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.

Conflict of Interest Statement: None declared.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received April 10, 2005; revised July 19, 2005; accepted July 22, 2005.





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