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Nutritional Epidemiology

Low Intake of Vitamin B-6 Is Associated with Increased Risk of Colorectal Cancer in Japanese Men^1,2

³ Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan and ⁴ Department of Public Health, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511 Japan

^* To whom correspondence should be addressed. E-mail: stsugane{at}ncc.go.jp.

	ABSTRACT

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

 
We investigated the association of dietary intakes of folate, vitamin B-6, vitamin B-12, and methionine with the risk of colorectal cancer in a large prospective cohort study of middle-aged Japanese men and women. A total of 81,184 subjects (38,107 men and 43,077 women) who participated in the Japan Public Health Center-based Prospective Study were followed from 1995–1998 to the end of 2002, during which 526 cases of colorectal cancer (335 men, 191 women) were newly identified. Dietary intake of nutrients was calculated using a 138-item self-administered FFQ. We observed a significant inverse association between vitamin B-6 intake and colorectal cancer in men. Compared with the lowest quartile, the multivariate hazard ratio (95% [CI]) in the highest quartile of intake was 0.69 (0.48–0.98) (P_trend = 0.03). Men who consumed 150 g/wk alcohol or more had twice the risk of colorectal cancer of those who drank less in the lowest quartile of vitamin B-6 intake, but risk due to alcohol intake was not higher in the highest quartile of vitamin B-6 intake. Vitamin B-6 intake and colorectal cancer were not associated in women. Folate and methionine intakes were not associated with colorectal cancer risk in men or women, but colorectal cancer risk tended to increase (P_trend = 0.05) with increasing intake of vitamin B-12 in men. Our results support previous evidence that low vitamin B-6 intake is associated with an increased risk of colorectal cancer. In particular, a higher intake of vitamin B-6 appears beneficial in men with higher alcohol intake.

	Introduction

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

One-carbon metabolism is a series of biochemical reactions that transfer single methyl groups from one site to another, synthesize nucleotides (purines and thymidylate) for DNA synthesis and repair, and methylate DNA (5). Folate is a primary methyl donor in this pathway and vitamins B-6 and B-12 are cofactors. Vitamin B-6 acts as a cofactor in the conversion of tetrahydrofolate to 5,10-methylene tetrahydrofolate and vitamin B-12 acts as a cofactor for methionine synthase, which remethylates homocysteine to methionine. Methionine, which is also ingested in the diet, is a precursor of S-adenosylmethionine, a methyl donor for DNA methylation. Vitamin B-6 is also a cofactor for cystathionine-ß-synthase, which synthesizes glutathionine from homocysteine via cystathionine and cysteine. Low dietary intake of these nutrients may result in colon carcinogenesis via the induction of aberrations in DNA methylation and synthesis (6–8). Alcohol intake has been shown to interfere with this pathway (9,10).

The results of a number of prospective cohort studies suggest an inverse association between folate intake and colorectal cancer (11–16), but not all (17–20). The association between vitamin B-6 and colorectal cancer is still inconsistent (13,15,19,21) and the evidence that vitamin B-12 and methionine affect colon cancer is limited. To our knowledge, moreover, no evidence has been provided for a protective effect of these nutrients in Asian populations.

We investigated the association of dietary intakes of folate, vitamin B-6, vitamin B-12, and methionine with the risk of colorectal cancer in a large prospective cohort study in middle-aged Japanese men and women.

	Subjects and Methods

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

 
    Study population. The Japan Public Health Center-based Prospective Study (JPHC Study)⁶ is an ongoing population-based cohort study begun in 1990–1994 to investigate cancer, cardiovascular diseases, and other lifestyle-related diseases in the residents of 11 public health center areas throughout Japan. Details of the study design have been provided elsewhere (22). The study was approved by the Institutional Review Board of the National Cancer Center, Tokyo, Japan.

The subjects of this study were JPHC study participants who responded to 5-y follow-up self-administered questionnaire surveys in 1995–1999 at age 45–74 y. A total of 47,400 men and 53,538 women responded (response rate, 75%). Subjects in one public health center area that does not collect information on cancer incidence were excluded.

    Exposure assessment. The FFQ used in the follow-up surveys was designed to estimate dietary intake from 138 food items and was validated for the estimation of various nutrients and food groups (23). The questionnaire included data on demographics, lifestyle, occupation, height, weight, smoking, alcohol consumption, physical activity, working hours, and stress.

In the FFQ, subjects were questioned about how often they consumed the individual food items (frequency of consumption) and representative relative sizes compared with standard portions. Response choices for frequency were never, 1–3 times/mo, 1–2 times/wk, 3–4 times/wk, 5–6 times/wk, once/d, 2–3 times/d, 4–6 times/d, and 7 times/d or more, and sizes relative to a standard portion were small (50% smaller than standard), medium (same as standard), and large (50% larger).

White rice intake was determined in terms of the relative size of the rice bowl used and the frequency of intake, with the 9 choices of <1 bowl/d to 10 bowls/d. The 6 choices for miso soup intake frequency were almost never, 1–3 times/mo, 1–2 times/wk, 3–4 times/wk, 5–6 times/wk, or daily and the amount was given in 9 categories ranging from <1 to 10 bowls/d (24).

Daily food intake was calculated by multiplying frequency by standard portion and relative size for each food item in the FFQ. Daily intakes of nutrients were calculated using the Fifth Revised and Enlarged Edition of the Standard Tables of Food Composition in Japan (25). The FFQ included questions on supplement use, but nutrient intake from supplements was not included in analyses, because no comprehensive database for supplements was available. Because very few folic acid or methionine supplements were available at the time of the study in Japan, the intake from the supplement for those nutrients is considered minimal. It is also noteworthy that no fortification program of folic acid or 3 other nutrients were instituted in Japan. The validity of folate, vitamin B-6, vitamin B-12, and methionine intakes estimated from the FFQ was evaluated in a subsample of the cohort by comparing the estimated intake according to the FFQ to that in the consecutive 7-d dietary records of the 4 seasons (26). Rank correlations after energy adjustment by the residual method were 0.35–0.50 for folate, 0.36–0.47 for vitamin B-6, 0.27–0.35 for vitamin B-12, and 0.20–0.31 for methionine.

    Identification of colorectal cancer. Incidence data on colorectal cancer were collected for the JPHC cancer registry through 2 data sources: periodic institutional reports from local major hospitals and population-based cancer registries. When subjects died, information on cancer incidence was supplemented with mortality data, i.e. death certificates, from the Ministry of Health, Labor and Welfare. The proportion of cases for which information was available from a death certificate only was 2.6% for colorectal cancer and 4.9% for all cancer. These ratios were considered satisfactory compared with the international standard (27). Cases of colorectal cancer were extracted from the JPHC cancer registry based on the following site codes of the Third Edition of the International Classification of Diseases for Oncology: C180–C189 for colon cancer, and C199 and C209 for rectal cancer (28).

    Statistical analysis. Study subjects were followed through December 31, 2002 (mean follow-up period = 5.8 y). Those moving to other municipalities were also identified annually through residential registries in their public health center areas. Among study subjects, 10% moved outside the study area and 0.3% were lost to follow-up during the study period. Person-years of follow-up were determined from the follow-up survey until the date of diagnosis of colorectal cancer, the date of death, the date of moving out of the study area, or December 31, 2002, whichever occurred first. Ineligible subjects excluded after the baseline survey included non-Japanese residents (31 men and 20 women), those who had moved away before baseline (107 men and 69 women), those outside the age parameters (1 man and 5 women), and subjects registered in duplicate (2 men and 1 woman). We also excluded subjects with a self-reported history of cancer in the baseline and 5-y follow-up questionnaires and those diagnosed with cancer before the 5-y follow-up survey. Finally, we excluded subjects who reported energy intake in the upper or lower 2.5% of intake [(lower and upper cut-off: 4,155 and 17,602 kJ for men, respectively; 3,502 and 15,414 kJ for women, respectively], and those who had missing values in any of the answers on covariates. A total of 38,107 men including 335 cases and 43,077 women including 191 cases remained for analysis.

Hazard ratios (HR) and 95% [CI] of colorectal cancer for quartiles of each nutrient intake were estimated by the Cox proportional hazards model. The estimates were adjusted for the following confounding factors incorporated into the model: age (continuous), alcohol consumption (nondrinkers, 1–3 d/mo, 1–149 g/wk, 150–299 g/wk, 300 or more g/wk), smoking (never, past, current), BMI (continuous), physical activity (metabolic equivalent hours per day), vitamin supplement use (user, nonuser), calcium, vitamin D, red and processed meat intakes (energy-adjusted, continuous), and study area (10 public health center locales).

On entry of covariates into a statistical model, dietary calcium, vitamin D, and red and processed meat (beef, pork, ham, sausage, bacon, and luncheon meat) intakes were adjusted for total energy intake using the residual method (29). Dietary intakes of these nutrients and foods was associated with intakes of folate, vitamin B-6, vitamin B-12, and methionine in the study subjects and has been suggested as the potential risk factor of the colorectal cancer by prior studies (30–32). Age, alcohol consumption, smoking, BMI (33,34), and physical activity (35) were predictors in this population. Linear trends for HR were tested by a 2-sided test, with 0.05 as the significance level using the median value in each category.

We also estimated HR referent to the group with low alcohol consumption (0–149 g/wk) and the lowest nutrient intake. We conducted the stratified analysis by alcohol consumption (weekly consumption of 0–149 g and 150 g) to obtain P_trend for each level of alcohol consumption. In addition, we tested the interaction between alcohol and nutrient intakes using the interaction term generated by multiplying alcohol consumption (0–149 g/wk and 150 g/wk) and the quartile of the nutrient intake. To obtain P for interaction, Wald's test was used to calculate the difference between chi-square distributions with and without interaction term. The results for the stratified analyses were presented only for men because of the low number of women who consumed alcohol at this level. All statistical analyses were conducted using SAS software (version 9.1; SAS Institute).

	Results

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

 
Men and women with higher intakes of folate, vitamins B-6 and B-12, and methionine were older, consumed less alcohol, and had higher dietary intakes of calcium and vitamin D (Table 1). Those with higher intakes of folate, vitamin B-6, and vitamin B-12 had higher intakes of fruits and vegetables. Those with higher intakes of vitamin B-12 and methionine consumed more red and processed meat. Those with higher intakes of folate, vitamin B-6, and methionine were less likely to be smokers, whereas those with a higher intake of vitamin B-12 were more likely to smoke.

	Discussion

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

Five prospective studies have investigated the association of colorectal cancer and vitamin B-6 intake in women. Larsson et al. (15) reported a decreasing risk of colon and rectal cancers in Swedish women with increasing vitamin B-6 intake, particularly in those who drank alcohol. Zhang et al. (13) reported an inverse association between vitamin B-6 intake and colorectal cancer in U.S. women who did not use multivitamin supplements. In the Iowa Women's Health Study, Harnack et al. (19) reported no association between vitamin B-6 intake and colorectal cancer, but women with a high intake of both folate and vitamin B-6 had a lower risk of proximal colon cancer. A nested case-control study that investigated the association between methylenetetrahydrofolate reductase (MTHFR) and colorectal cancer in the Multiethnic Cohort Study showed a lower risk of colorectal cancer in the group that consumed more vitamin B-6, regardless of genotype (21). Results from another nested case-control study in the Nurses' Health Study suggested an inverse association between colorectal cancer and both dietary intake and the plasma concentration of vitamin B-6 (36).

The present results support this previous evidence for the potential benefit of vitamin B-6 in the prevention of colorectal cancer in those who drink alcohol. Although the previous studies were conducted in women who consumed alcohol, we confirm here that the risk is the same in men. Meanwhile, we observed no association in women, possibly because of the small percentage of women who consume alcohol in Japan.

Some (11–16) but not all (17–20) prospective cohort studies have suggested an inverse association between folate intake and colon and rectal cancers. A recent meta-analysis of folate intake and colorectal cancer has revealed that the association is limited to intake from diet only and not to total nutrient intakes from diet and supplements (37). The lack of association in our Japanese subjects may have been because their folate exposure was quite high. A null association due to an insufficient number of folate-deficient subjects was also seen in a nested-case control study investigating plasma folate level and the risk of colorectal cancer in JPHC study participants (T. Otani, M. Iwasaki, S. Sasazuki, M. Inoue, S. Tsugane, unpublished data,). The association may have been distorted by factors known to alter folate metabolism, such as genotype; a nested case-control study (21) and several case-control studies (38–41) have investigated the potential interaction of MTHFR and folate intake, but results have been inconsistent. At this point, data about genetic polymorphism is not available in our study.

With regard to vitamin B-12 and colorectal cancer, none of the previous studies identified an association (19,21,38,39). Here, in contrast, colorectal cancer was positively associated with vitamin B-12 intake. Given that our subjects who consumed higher amounts of vitamin B-12 were more likely to be smokers, that smoking confers a strong risk for colorectal cancer in this population (42), and that the association was stronger in those who were heavy alcohol drinkers (who were also likely to smokers) (42), it is possible that the influence of smoking remained even after adjustment. Because the physiological level of vitamin B-12 is determined largely by absorption and utilization (43), the association with vitamin B-12 may actually represent the effect of smoking rather than dietary intake.

One of 3 case-control studies reported an inverse association between methionine intake and colorectal cancer in conjunction with MTHFR polymorphism (38), whereas the other 2 reported a null association. A cohort study that investigated intake alone also showed no association (19), whereas the other cohort study suggested that the combination of low methionine, high alcohol, and low folate intakes may be a risk factor for colon cancer (44). In the present study, meaningful results for the combination of nutrients could not be obtained due to an insufficient number of subjects. In contrast, animal studies indicated that low methionine intake inhibits colonic tumor development (45) and increases blood glutathione (46,47), which detoxifies carcinogenic compounds and protects cells from oxidative DNA damage. A tendency for higher risk in the highest and lowest methionine intake quartiles was found in women in our study (P_trend = 0.06).

Additional analyses performed following exclusion of the 10% of subjects who used vitamin supplements produced similar results to those for all subjects. The 2003 National Health and Nutrition Survey in Japan reported that 10% of the Japanese population took some kind of dietary supplement; one-half of the 10% took vitamin B-6 (48). Mean intake from supplements and fortified foods in supplement users aged 20 y or older was 15.7 mg, >10 times the 1.27 mg in nonusers. Information about folate, vitamin B-12, and methionine intakes from supplements was not available in the National Health and Nutrition Survey. Ogata et al. (49) reported that if vitamin B-1 intake from food plus supplements is categorized into quartiles, all supplement users will be in the highest intake category; in other words, intake from supplements is at megadose levels relative to dietary intake. Misclassification due to such additional intake would tend to attenuate associations between nutrients and disease, especially if the percentage of supplement users is high.

A protective effect for vitamin B-6 in those who drink alcohol is biologically plausible. Specifically, higher vitamin B-6 intake may be necessary in this population because: 1) alcohol interferes with the absorption of vitamin B-6 and promotes its degradation; 2) alcohol inhibits methionine synthase, which synthesizes methionine from homocysteine in 1-carbon metabolism; and 3) alcohol intake lowers physiological levels of glutathione. Vitamin B-6 is a coenzyme in the synthesis of glutathione from homocysteine (9,10).

Dietary folate in our population was derived from various foods of both plant and animal origin, such as spinach, rice, green tea, cabbage, and eggs (50). Vitamin B-6 was derived from rice, tuna fish, potatoes, beer, and sake (Japanese rice-wine). The major source of vitamin B-12 was primarily from various types of fish. We investigated the association between the dietary intake of those foods that contribute to vitamin B intake and the risk of colorectal cancer, because B vitamins are found in many foods rather than a few particular foods, so the association with any particular food is weak.

This study had several limitations. Individuals with a high intake of vitamin B-6 may have been at lower risk of colorectal cancer due to other health habits and behaviors. The likelihood of this was reduced, however, by the multivariable adjustment for potential confounding variables, including other colorectal cancer risk factors, physical activity, alcohol intake, selected dietary variables, total energy intake, and supplement use. Another limitation was that measurement errors in assessing nutrient intake are unavoidable. Measurement error in the FFQ may have resulted in the misclassification of individual intakes. Such random errors of measurement tend to result in null rather than spurious associations.

In conclusion, dietary intake of vitamin B-6 was associated with a reduced risk of colorectal cancer in Japanese middle-aged men, primarily in those who consume alcohol. Higher intake of vitamin B-6 may be beneficial in those consuming >150 g alcohol/wk.

	FOOTNOTES

 
¹ Supported by grants-in-aid for Cancer Research and for the 3rd Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan. Junko Ishihara was awarded a research resident fellowship from the Foundation for the Promotion of Cancer Research (Japan) for the 3rd Term Comprehensive 10-year Strategy for Cancer Control.

² Author disclosures: J. Ishihara, T. Otani, M. Inoue, M. Iwasaki, S. Sasazuki, and S. Tsugane, no conflicts of interest.

⁵ Members of Japan Public Health Center-based Prospective Study Group: S. Tsugane, M. Inoue, T. Sobue, T. Hanaoka, National Cancer Center, Tokyo; J. Ogata, S. Baba, T. Mannami, A. Okayama, National Cardiovascular Center, Suita; K. Miyakawa, F. Saito, A. Koizumi, Y. Sano, I. Hashimoto, T. Ikuta, Iwate Prefectural Ninohe Public Health Center, Ninohe; Y. Miyajima, N. Suzuki, S. Nagasawa, Y. Furusugi, N. Nagai, Akita Prefectural Yokote Public Health Center, Yokote; H. Sanada, Y. Hatayama, F. Kobayashi, H. Uchino, Y. Shirai, T. Kondo, R. Sasaki, Y. Watanabe, Y. Miyagawa, Nagano Prefectural Saku Public Health Center, Saku; Y. Kishimoto, E. Takara, T. Fukuyama, M. Kinjo, M. Irei, H. Sakiyama, Okinawa Prefectural Chubu Public Health Center, Okinawa; K. Imoto, H. Yazawa, T. Seo, A. Seiko, F. Ito, F. Shoji, Katsushika Public Health Center, Tokyo; A. Murata, K. Minato, K. Motegi, T. Fujieda, Ibaraki Prefectural Mito Public Health Center, Mito; K. Matsui, T. Abe, M. Katagiri, M. Suzuki, K. Matsui, Niigata Prefectural Kashiwazaki Public Health Center, Kashiwazaki; M. Doi, A. Terao, Y. Ishikawa, Kochi Prefectural Chuo-higashi Public Health Center, Tosayamada; H. Sueta, H. Doi, M. Urata, N. Okamoto, F. Ide, Nagasaki Prefectural Kamigoto Public Health Center, Arikawa; H. Sakiyama, N. Onga, H. Takaesu, M. Uehara, Okinawa Prefectural Miyako Public Health Center, Hirara; F. Horii, I. Asano, H. Yamaguchi, K. Aoki, S. Maruyama, M. Ichii, M. Takano, Osaka Prefectural Suita Public Health Center, Suita; S. Matsushima, S. Natsukawa, Saku General Hospital, Usuda; M. Akabane, Tokyo University of Agriculture, Tokyo; M. Konishi, K. Okada, Ehime University, Matsuyama; H. Iso, Osaka University, Suita; K. Yamagishi, Y. Honda, Tsukuba University, Tsukuba; H. Sugimura, Hamamatsu University, Hamamatsu; Y. Tsubono, Tohoku University, Sendai; the late M. Kabuto, National Institute for Environmental Studies, Tsukuba; S. Tominaga, Aichi Cancer Center Research Institute, Nagoya; M. Iida, W. Ajiki, Osaka Medical Center for Cancer and Cardiovascular Disease, Osaka; S. Sato, Osaka Medical Center for Health Science and Promotion, Osaka; N. Yasuda, Kochi University, Nankoku; S. Kono, Kyushu University, Fukuoka; K. Suzuki, Research Institute for Brain and Blood Vessels Akita, Akita; Y. Takashima, Kyorin University, Mitaka; E. Maruyama, Kobe University, Kobe; the late M. Yamaguchi, Y. Matsumura, S. Sasaki, S. Watanabe, National Institute of Health and Nutrition, Tokyo; T. Kadowaki, Tokyo University, Tokyo; Y. Kawaguchi, Tokyo Medical and Dental University, Tokyo; and H. Shimizu, Sakihae Institute, Gifu.

⁶ Abbreviations used: HR, hazard ratio; JPHC Study, Japan Public Health Center-based Prospective Study; MTHFR, methylenetetrahydrofolate reductase.

Manuscript received 22 January 2007. Initial review completed 13 March 2007. Revision accepted 8 May 2007.

	LITERATURE CITED

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