Vitamin B 6 Intake, Alcohol Consumption, and Colorectal Cancer: A Longitudinal Population-Based Cohort of Women

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1 GASTROENTEROLOGY 2005;128: Vitamin B 6 Intake, Alcohol Consumption, and Colorectal Cancer: A Longitudinal Population-Based Cohort of Women SUSANNA C. LARSSON,* EDWARD GIOVANNUCCI, and ALICJA WOLK* *Division of Nutritional Epidemiology, the National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; and Departments of Nutrition and Epidemiology, Harvard School of Public Health, and Channing Laboratory, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts Background & Aims: Vitamin B 6 has a crucial role in 1-carbon metabolism, which involves DNA synthesis and DNA methylation. Aberrations in these processes have been implicated in colorectal carcinogenesis. We examined the association between long-term dietary vitamin B 6 intake and risk of colorectal cancer and whether this association is modified by consumption of alcohol, which may disrupt 1-carbon metabolism. Methods: Our study population comprised 61,433 women in the population-based Swedish Mammography Cohort. The women were aged 40 to 76 years, had no history of cancer, and completed a food-frequency questionnaire at baseline in Dietary information was updated in During a mean follow-up of 14.8 years, 805 incident colorectal cancer cases were diagnosed. Results: After controlling for age and other potential confounders, long-term intake of dietary vitamin B 6 was significantly inversely associated with risk of colorectal cancer (P value for trend.002). Compared with women in the lowest quintile of vitamin B 6 intake, those in the highest quintile had a 34% lower risk (multivariate rate ratio, 0.66; 95% confidence interval, ). The association was most pronounced among women with moderate to high alcohol consumption. The multivariate rate ratio of colorectal cancer comparing extreme quintiles of vitamin B 6 intake was 0.28 (95% confidence interval, ) among women who consumed >30 g/wk of alcohol (approximately equivalent to 2 drinks per week). Conclusions: Findings of this study suggest that vitamin B 6 may play a role in the prevention of colorectal cancer, particularly among women who drink alcohol. Vitamin B 6 in its principal active form, pyridoxal 5=-phosphate, is involved in nearly 100 enzymatic reactions. 1 One function of vitamin B 6 that makes it potentially important in carcinogenesis relates to its role in 1-carbon metabolism, which involves the transfer of 1-carbon groups for DNA synthesis and DNA methylation (Figure 1). In these metabolic pathways, vitamin B 6 is a crucial coenzyme of serine hydroxymethyltransferase for the synthesis of 5,10-methylenetetrahydrofolate. This form of folate is needed for the synthesis of nucleotides (purines and thymidylate) for DNA synthesis and repair. Alternatively, 5,10-methylenetetrahydrofolate can be reduced to 5-methyltetrahydrofolate and used for the remethylation of homocysteine to methionine, a reaction facilitated by methionine synthase (MS). Methionine is a precursor of S-adenosylmethionine, the universal methyl group donor for methylation reactions, including DNA methylation. 2 Vitamin B 6 deficiency has been associated with substantially impaired 1-carbon metabolism in animals. 3 Thus, an inadequate vitamin B 6 intake might lead to disruption of DNA synthesis, repair, and methylation, any of which may enhance colorectal carcinogenesis. 2,4 Apart from its role in the synthesis, repair, and methylation of DNA, vitamin B 6 is necessary for the synthesis of glutathione from homocysteine via cystathionine and cysteine. These reactions are facilitated by 2 vitamin B 6 -dependent enzymes: cystathionine -synthase and -cystathionase (Figure 1). Glutathione is a cofactor of the glutathione S-transferases and glutathione peroxidases, which function in the detoxification of many carcinogenic compounds and in the protection of cells from oxidative DNA damage. 5 7 Vitamin B 6 has been shown to reduce oxidative stress as well as cell proliferation and angiogenesis, and moderate doses of vitamin B 6 have been shown to suppress colorectal carcinogenesis in mice given injections of a carcinogen. 8,9 Alcohol consumption may interfere with 1-carbon metabolism by influencing the absorption and degradation of vitamin B 6 and folate and by inhibition of MS In addition, high alcohol consumption has been associated with lower glutathione levels 20 (Figure 1). Many epidemiological studies have reported that adequate folate intake may be important in the prevention of Abbreviations used in this paper: CI, confidence interval; MS, methionine synthase; RR, rate ratio by the American Gastroenterological Association /05/$30.00 doi: /j.gastro

2 June 2005 VITAMIN B 6 INTAKE AND COLORECTAL CANCER 1831 who had extreme total energy intake estimates ( 3 SDs from the mean value for log e -transformed energy) were also excluded. After these exclusions, the study cohort comprised 61,433 women at the start of follow-up. This study was approved by the Ethics Committees at the Uppsala University Hospital and the Karolinska Institutet, Stockholm. Figure 1. Overview of the role of vitamin B 6 in DNA synthesis, DNA methylation, detoxification of carcinogens, and protection against oxidative DNA damage. CH 3, methyl group; CBS, cystathionine -synthase; CpG, cytosine-guanine dinucleotide sequence; -Cys, -cystathionase; dtmp, deoxythymidylate monophosphate; dump, deoxyuridylate monophosphate; MS, methionine synthase; MTHFR, 5,10- methylenetetrahydrofolate reductase; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; SHMT, serine hydroxymethyltransferase; TS, thymidylate synthase; 5,10-methyleneTHF, 5,10-methylenetetrahydrofolate; 5-methylTHF, 5-methyltetrahydrofolate. colorectal cancer and colorectal adenomas, particularly among individuals who consume alcohol Few studies, however, have examined the relationship between vitamin B 6 intake and colorectal cancer, and only 2 studies 25,26 have investigated whether the association is modified by alcohol consumption. Furthermore, only 1 study 26 has evaluated long-term vitamin B 6 intake in relation to colorectal cancer risk. In this study, we sought to evaluate the association between long-term dietary vitamin B 6 intake (ie, vitamin B 6 from food sources) and colorectal cancer risk and its modification by alcohol consumption in the Swedish Mammography Cohort, a large population-based prospective cohort with repeated measurements of diet. Materials and Methods Study Population The Swedish Mammography Cohort is a populationbased cohort study established between 1987 and 1990, when all 90,303 women (then aged 40 to 76 years and living in Västmanland or Uppsala Counties, central Sweden) received a mailed questionnaire that solicited data on diet, educational level, weight, and height; a total of 66,651 women, representing 74% of the source population, returned a completed questionnaire. A follow-up questionnaire sent to all surviving participants in 1997 was expanded to include information on family history of colorectal cancer, smoking, physical activity, and use of dietary supplements and aspirin. The 1997 questionnaire also included a comprehensive survey of diet. For these analyses, we excluded women with an erroneous National Registration Number and those with cancer (except nonmelanoma skin cancer) diagnosed before baseline. Women Assessment of Diet A self-administered food-frequency questionnaire with 67 and 96 food items was mailed to participants at baseline ( ) and in 1997, respectively. Participants were asked how often, on average, they had consumed each type of food or beverage during the past 6 months (baseline questionnaire) or the past year (1997 questionnaire), by using 8 predefined response categories. For foods commonly consumed (eg, milk, bread, and butter), there were open-ended questions. Nutrient calculations were based on the mean values of agespecific ( 53, 53 65, and 66 years) portion sizes of scaledweighted foods that were recorded for 5922 days by 213 women randomly chosen from the study area. For each woman, we computed nutrient intake by multiplying the frequency response by the nutrient content of the age-specific servings. Values for the nutrient content in foods were obtained from the Swedish National Food Administration Database. 29 All nutrient intakes, except alcohol, were adjusted for total energy intake by using the residual method. 30 In a study of the validity of the food-frequency questionnaire among 129 women randomly selected from the cohort, Pearson correlation coefficients between estimates from the average of four 1-week diet records and the dietary questionnaire were 0.5 for dietary vitamin B 6 and 0.9 for alcohol (A.W., unpublished data). Among this group of women, the mean estimated dietary vitamin B 6 intake was 1.7 mg/day (SD, 0.4 mg/day). Case Ascertainment and Follow-up of the Cohort By using the National Registration Numbers of the participants, incident colorectal cancer cases were identified by computerized record linkages with the National Swedish Cancer Registry and the Regional Cancer Registry covering the study area. Follow-up for cancers through these registries is nearly 100% complete. 31 Ascertainment of deaths in the cohort and the date when a participant moved out of the study area was accomplished by matching with the Swedish Death and Population Registries. Colon cancers were defined as tumors occurring above the peritoneal delineation of the abdominal cavity, and rectal cancers were tumors occurring below this delineation. Women who had both colon and rectal cancer were excluded from subsite-specific analyses but were included in the overall analyses of colorectal cancer. Data Analysis Person-time of follow-up for each woman was computed from the date of her entry into the cohort until the date

3 1832 LARSSON ET AL GASTROENTEROLOGY Vol. 128, No. 7 of a colorectal cancer diagnosis, death from any cause, the date of leaving the study area, or the end of follow-up (June 30, 2004), whichever occurred first. We categorized the women into quintiles according to their dietary vitamin B 6 intake and computed incidence rates of colorectal cancer by dividing the number of incident colorectal cancer cases by person-years of follow-up in each quintile. The rate ratios (RRs) were calculated by dividing the incidence rate in each of the upper quintiles by the incidence rate in the lowest quintile. To best represent long-term dietary intake and to reduce random within-person variation, we used repeated measures of diet in the analyses. 32 Specifically, the incidence of colorectal cancer from 1987 through 1997 was related to the intake reported on the baseline questionnaire, and the incidence from 1998 through June 2004 was related to the average intake reported on the baseline and the 1997 questionnaires. The RRs with corresponding 95% confidence intervals (CIs) were estimated with the Cox proportional hazards model. 33 Age in months at baseline and the year of entry into the cohort were used as stratification variables, thereby creating a time metric that simultaneously accounts for age, calendar time, and time since entry into the cohort. In multivariate models, we included body mass index, educational level, red meat consumption, and intakes of saturated fat, calcium, folate, -carotene, and cereal fiber. Intake of total energy was also included in the multivariate models to minimize extraneous variation introduced by underreporting or overreporting in the food-frequency questionnaire. 30 In additional analyses, we further adjusted for family history of colorectal cancer, smoking, physical activity, and the use of dietary supplements and aspirin by using data from the 1997 questionnaire. Tests for linear trend were conducted by treating vitamin B 6 intake as a continuous variable. We used restricted cubic spline regressions with 5 knots to flexibly model the relation between vitamin B 6 intake and risk of colorectal cancer, thus avoiding the need for prior specification of the risk function or the location of a threshold exposure value. 34 We evaluated whether the association between vitamin B 6 intake and colorectal cancer was modified by alcohol consumption through stratified analyses. The P value for test of interaction was obtained from a likelihood ratio test. The Wald statistic was used to test whether the associations differed for colon and rectal cancers. 35 All analyses were performed with SAS (version 9.1; SAS Institute Inc, Cary, NC), and all P values were 2 tailed. Results During a mean follow-up of 14.8 years, 805 women received a diagnosis of colorectal cancer, including 547 colon cancers (249 proximal colon, 170 distal colon, and 128 unspecified) and 252 rectal cancers; 6 cases were diagnosed as both colon and rectal cancer. The age range of the participants at the time of diagnosis of colorectal cancer was years (mean, 68 years; SD, 9.1 years). The baseline characteristics of the study population by dietary vitamin B 6 intake are presented in Table 1. Women with a higher vitamin B 6 intake were slightly more likely to have a postsecondary education than were women with a lower intake. Intake of vitamin B 6 was significantly (P.0001) inversely correlated with intakes of saturated fat (Spearman correlation coefficient [r] 0.38) and the percentage of calories from fat (r 0.45) and was positively correlated with intakes of folate (r 0.53), -carotene (r 0.34), and red meat (r 0.09). The age-adjusted and multivariate RRs of colorectal cancer according to cumulative average vitamin B 6 intake are shown in Table 2. Compared with women in the bottom quintile of vitamin B 6 intake, the multivariate RR for those in the top quintile was 0.66 (95% CI, ; P value for trend.002). The results were Table 1. Baseline Characteristics According to Dietary Vitamin B 6 Intake Among the 61,433 Participants in the Swedish Mammography Cohort a Quintiles of dietary vitamin B 6 intake (mg/day) b Characteristic Age (y) Body mass index (kg/m 2 ) Postsecondary education (%) Dietary intake Calories from fat (%) Saturated fat (g/day) b Alcohol (g/wk) Calcium (mg/day) b Folate ( g/day) b Carotene (mg/day) b Cereal fiber (g/day) b Red meat (g/day) a Values are means unless otherwise indicated. All values (except age) are standardized to the age distribution of the study population. b Nutrients are adjusted to 1700 kcal, the mean energy intake among a subsample of 129 cohort members who kept 28-day diet records; in this group of women, the mean estimated daily dietary vitamin B 6 intake was 1.7 mg/day (SD, 0.4 mg/day), which equals 1.0 mg/1000 kcal.

4 June 2005 VITAMIN B 6 INTAKE AND COLORECTAL CANCER 1833 Table 2. Rate Ratio of Colorectal Cancer According to Cumulative Dietary Vitamin B 6 Intake Quintiles of dietary vitamin B 6 intake (mg/day) Variable P value for trend a Person-years of follow-up 189, , , , ,434 Colorectal cancer Number of cases Age-adjusted RR (95% CI) 1.00 (reference) 1.00 ( ) 0.86 ( ) 0.83 ( ) 0.77 ( ).01 Multivariate RR (95% CI) b 1.00 (reference) 0.96 ( ) 0.80 ( ) 0.74 ( ) 0.66 ( ).002 Colon cancer c Number of cases Age-adjusted RR (95% CI) 1.00 (reference) 1.10 ( ) 0.82 ( ) 0.95 ( ) 0.87 ( ).16 Multivariate RR (95% CI) b 1.00 (reference) 1.08 ( ) 0.80 ( ) 0.89 ( ) 0.75 ( ).04 Rectal cancer c Number of cases Age-adjusted RR (95% CI) 1.00 (reference) 0.86 ( ) 0.93 ( ) 0.63 ( ) 0.63 ( ).04 Multivariate RR (95% CI) b 1.00 (reference) 0.76 ( ) 0.79 ( ) 0.52 ( ) 0.50 ( ).02 CI, confidence interval; RR, rate ratio. a P values for trend were calculated with the Wald statistic by using vitamin B 6 intake as a continuous variable. b Adjusted for age (in months; continuous), body mass index (quartiles), education (less than high school, high school, or university), total energy intake (continuous), and quartiles of intakes of red meat, saturated fat, calcium, folate, -carotene, and cereal fiber. c The sum of colon and rectal cancers (total of 799 cases) does not add to the total number of colorectal cancers (total of 805 cases) because 6 cases were diagnosed as both colon and rectal cancer and were excluded from subsite-specific analyses. not materially altered after further adjustment for consumption of fruits and vegetables (RR, 0.66; 95% CI, ) or for intakes of alcohol, methionine, and vitamins B 12, C, and D (RR, 0.67; 95% CI, ). The inverse association with vitamin B 6 intake also remained essentially unchanged after additional controlling for a family history of colorectal cancer, smoking, physical activity, and use of multivitamin supplements and aspirin (RR, 0.65; 95% CI, ). Results of analyses using the baseline diet only were similar to those obtained with the cumulative average diet. The regression spline indicated an inverse dose-response relationship between vitamin B 6 intake and colorectal cancer risk, with no evidence of a threshold exposure value (Figure 2). The reduction in cancer risk associated with a high vitamin B 6 intake was somewhat stronger for the rectum than the colon (Table 2), but results of a test for difference by anatomic site were not statistically significant (P.25 for the highest intake quintile). To assess the potential modifying effect of alcohol consumption on the association between vitamin B 6 intake and colorectal cancer risk, analyses were repeated within subgroups defined by this variable (Table 3). The inverse association between vitamin B 6 intake and colorectal cancer risk was particularly strong among women with high alcohol consumption. The multivariate RR comparing extreme quintiles of vitamin B 6 intake was 0.28 (95% CI, ) among women who consumed at least 30 g/wk of alcohol (approximately equivalent to 2 drinks per week). The comparable RRs were 0.32 (95% CI, ) for colon cancer and 0.21 (95% CI, ) for rectal cancer. A test for interaction between vitamin B 6 intake and alcohol consumption in relation to colorectal cancer risk was statistically significant (P.008). We found no overall association between alcohol consumption and risk of colorectal cancer. However, consumption of alcohol was positively associated with risk Figure 2. Multivariate rate ratio of colorectal cancer as a function of dietary vitamin B 6 intake. Data were fitted by a restricted cubic spline Cox proportional hazards model, adjusted for age (in months; continuous), body mass index (quartiles), education (less than high school, high school, or university), total energy intake (continuous), and quartiles of intakes of red meat, saturated fat, calcium, folate, -carotene, and cereal fiber. The solid line represents point estimates; dashed lines represent 95% confidence intervals.

5 1834 LARSSON ET AL GASTROENTEROLOGY Vol. 128, No. 7 Table 3. Multivariate Rate Ratio of Colorectal Cancer According to Cumulative Dietary Vitamin B 6 Intake Stratified by Alcohol Consumption Quintiles of dietary vitamin B 6 intake (mg/day) Alcohol consumption P value for trend a 10 g/wk Number of cases Multivariate RR (95% CI) b 1.00 (reference) 1.25 ( ) 0.97 ( ) 0.96 ( ) 0.84 ( ) to 30 g/wk Number of cases Multivariate RR (95% CI) b 1.00 (reference) 0.79 ( ) 0.83 ( ) 0.66 ( ) 0.65 ( ) g/wk c Number of cases Multivariate RR (95% CI) b 1.00 (reference) 0.57 ( ) 0.44 ( ) 0.45 ( ) 0.28 ( ).0002 P for interaction d.008 CI, confidence interval; RR, rate ratio. a P values for trend were calculated with the Wald statistic by using vitamin B 6 intake as a continuous variable. b Multivariate rate ratios adjusted for age (in months; continuous), body mass index (quartiles), education (less than high school, high school, or university), total energy intake (continuous), and quartiles of intakes of red meat, saturated fat, calcium, folate, -carotene, and cereal fiber. Age-adjusted results are not presented because the results are similar to the multivariate results. c The 50th and 75th percentiles of alcohol consumption in the subgroup of women drinking 30 g/wk of alcohol were 43.1 and 61.2 g/wk, respectively. d P value for the test for interaction between vitamin B 6 intake and alcohol consumption in relation to colorectal cancer risk was obtained from a likelihood ratio test. among women with a low vitamin B 6 intake; the multivariate RRs of colorectal cancer among women in the lowest quintile of vitamin B 6 for increasing quartiles of alcohol consumption (no consumption, 2.2 g/day, g/day, and 4.5 g/day) were 1.00, 1.13 (95% CI, ), 1.83 (95% CI, ), and 1.77 (95% CI, ), respectively (P for trend.02). Our findings were similar when we excluded colorectal cancer cases that occurred within the first 2 years of follow-up. Furthermore, excluding women who reported use of multivitamins and other vitamin supplements containing vitamin B 6 (approximately 29% of women in 1997) did not change the results materially; the multivariate RR of colorectal cancer comparing the highest with the lowest quintile of vitamin B 6 intake from foods was 0.64 (95% CI, ) among women who did not use vitamin supplements. Discussion In this large population-based cohort of women, we observed a significant inverse dose-response relationship between long-term dietary vitamin B 6 intake and risk of colorectal cancer. The inverse association was particularly pronounced among women who consumed moderate to high amounts of alcohol ( 30 g/wk). Among these women, we observed a 72% lower risk of colorectal cancer for women in the highest quintile of vitamin B 6 intake compared with those in the lowest quintile. To our knowledge, only 2 previous cohort studies have investigated the possible role of vitamin B 6 in the risk of colorectal cancer. 26,27 In the Nurses Health Study, Wei et al 26 recently observed significant inverse associations between plasma pyridoxal 5=-phosphate levels and longterm intake of total vitamin B 6 and colorectal cancer risk. They also found an inverse, albeit not statistically significant, association between plasma pyridoxal 5=-phosphate levels and colorectal adenomas. In the Iowa Women s Health Study, Harnack et al. 27 found no independent associations of vitamin B 6 or folate intake (measured at baseline) with colorectal cancer risk; however, women with high intakes of both vitamin B 6 and folate had a significant 35% decreased risk of proximal colon cancer. Most, but not all, 25 case-control studies have reported significant inverse associations between intake of vitamin B 6 and risk of colorectal adenomas 36,37 or colon cancer. 28 A high vitamin B 6 intake has also been associated with a lower risk of adenoma recurrence. 38 In this study, we found a significant interaction between long-term vitamin B 6 intake and alcohol consumption in relation to colorectal cancer risk; that is, women who consumed alcohol seemed to benefit most from a high vitamin B 6 intake. We also observed that alcohol consumption may increase the risk of colorectal cancer, especially among women with a low vitamin B 6 intake. In a recent pooled analysis of 8 cohort studies, 39 a positive association of alcohol consumption with colorectal cancer risk was restricted to individuals who did

6 June 2005 VITAMIN B 6 INTAKE AND COLORECTAL CANCER 1835 not take multivitamins, most of which contain vitamin B 6 and other B vitamins. A case-control study in the United States reported no overall significant association of vitamin B 6 intake with risk of colon cancer, but it found some evidence that a combination of high alcohol consumption and low intakes of vitamin B 6, folate, vitamin B 12, and methionine may increase the risk. 25 In a subpopulation of the Nurses Health Study, the association observed between plasma pyridoxal 5=-phosphate levels and the risk of colorectal neoplasia was not significantly modified by alcohol consumption. 26 However, both vitamin B 6 and folate intakes in the cohort of the US nurses were higher than in the cohort of Swedish women. Also, the present study was larger, so we had greater statistical power to observe a significant modification by alcohol consumption. An interaction between vitamin B 6 intake and alcohol consumption is biologically plausible. First, chronic alcohol consumption may interfere with the synthesis and transfer of 1-carbon groups needed for DNA synthesis and DNA methylation by reducing intestinal absorption and increasing renal excretion of vitamin B 6 and folate and by reducing the activity of MS (Figure 1). Vitamin B 6 deficiency has been observed in both rats 40 and humans 41 consuming alcohol. Second, chronic alcohol consumption decreases the levels of glutathione, 20 which is synthesized from homocysteine via a reaction facilitated by 2 vitamin B 6 -dependent enzymes (Figure 1). Decreased glutathione levels might enhance the susceptibility to DNA damage. However, this evidence is from studies on excessive chronic alcohol use and is thus not necessarily applicable to our results. The possible effect of moderate amounts of alcohol consumption on vitamin B 6 status and on 1-carbon metabolism needs more research. Besides alcohol consumption, the relationship between vitamin B 6 and colorectal cancer may be modified by polymorphisms of genes coding for enzymes involved in 1-carbon metabolism (Figure 1). Three case-control studies have investigated the interplay between vitamin B 6 intake and a polymorphism of 5,10-methylenetetrahydrofolate reductase, and they found that the risk of colorectal cancer 24,42 or adenomas 43 was 30% 60% lower among individuals with a high intake of vitamin B 6 and who were homozygous for the 677TT variant genotype. In another case-control study, women and men with a low dietary vitamin B 6 intake and who were homozygous for the 919GG variant genotype of MS had a 2 7-fold increased risk of adenoma, respectively; however, neither the risk estimates nor the tests for interaction between vitamin B 6 intake and the polymorphism were statistically significant. 44 The strengths of our study include a prospective population-based design, large sample size, and completeness of identification of cases through the Swedish Cancer Register system. The main limitation of this study was the lack of information on the use of vitamin supplements at baseline in , which may have resulted in some degree of misclassification of total vitamin B 6 intake (ie, from foods and supplements). However, the results did not change materially after participants were excluded who reported use of supplements containing vitamin B 6 in the 1997 questionnaire. Because dietary intake was assessed through self-administered food-frequency questionnaires, measurement errors are inevitable. By updating and averaging the repeated measurements of diet, we reduced within-person fluctuations and took into account changes over time, and this should reduce measurement errors. Some misclassification still exists, which would tend to weaken any true association. This study was observational; therefore, we cannot entirely rule out the possibility that the associations we observed were partly attributed to unmeasured factors or to residual confounding. Nonetheless, adjusting for a wide range of dietary and lifestyle factors did not alter the risk estimates appreciably, thus suggesting that uncontrolled confounding or residual confounding is unlikely to explain our findings. The recommended daily dietary intake of vitamin B 6 for nonpregnant women is 1.2 mg in Sweden 45 and mg in the United States. 46 The mean intake of dietary vitamin B 6 in our study population of Swedish women, as estimated from 28-day diet records kept by 129 cohort members, was 1.7 mg/day. Findings from our study suggest that women who consume alcohol may benefit from a vitamin B 6 intake above the recommendations. Foods high in vitamin B 6 include some fruits (eg, bananas) and vegetables, potatoes, fortified cereals, legumes, fish, chicken, and red meat. In conclusion, results from this large prospective cohort of women based on long-term diet suggest that a high vitamin B 6 intake may reduce the risk of colorectal cancer, particularly among women who consume alcohol. This finding may have important implications for the prevention of colorectal cancer, because many individuals consume alcohol and the population s vitamin B 6 status can be improved relatively easily through dietary modifications, vitamin supplementation, and fortification. Hence, further research is warranted on the interrelations among vitamin B 6, alcohol consumption, and polymorphisms of genes that code for enzymes involved in 1-carbon metabolism in relation to the risk of colorectal cancer.

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