In this large cohort of women, we observed no association between intakes of total folate and total vitamin B6 and the risk of colorectal cancer. However, we found an inverse association between intakes of dietary folate and dietary vitamin B6 and the risk of colorectal cancer among women who did not take these supplements.
Because of the prospective design, recall or selection biases are unlikely to explain our findings in this study, and the high follow-up rates minimize the concern that differential follow-up rates have affected our results. Symptoms of colorectal cancer might have caused some women to increase their intake of vitamins before clinical diagnosis. However, the similar results after exclusion of colorectal cancer cases diagnosed within the first two years of follow-up do not support this explanation. Although confounding by unknown variables cannot be excluded, it seems unlikely because adjustment for a number of potential risk factors for colorectal cancer had minimal effect on the relative risks. However, estimates of nutrient intake calculated from the food frequency questionnaire are subject to measurement error. Such error is most likely to be non-differential due to our prospective design and may result in attenuation of risk estimates. Since we assessed intakes of nutrients only at baseline, measurement error due to random withinperson variation may be inevitable. Finally, because the number of events was relatively modest, we had limited statistical power for stratified analyses and analyses according to tumor locations.
Although data are not totally consistent, the findings from prospective cohorts that have evaluated folate intake and the risk of colorectal cancer suggest an inverse association (9
), particularly among individuals with a high-alcohol diet. In the Nurses' Health Study, women with folate intake of >400 μg/day were found to have a significantly lower (31%) risk of colon cancer than women with intake of ≤200 μg/day (11
). Furthermore, women taking folic acid-containing multivitamins for ≥15 years were 75% less likely to develop colon cancer than were women who did not take multivitamins (11
). Two (12
) of three (10
) prospective studies have also suggested that high folate blood levels are related to reduced risk of colorectal cancer. Several case-control studies have reported on folate intake and colorectal cancer risk (19
); most have found a lower risk of colorectal cancer associated with higher folate intake (19
). Compared with other cohorts in the North America (39
), the level of alcohol intake in the Women's Health Study was much lower, which may limit our power to detect a difference in the association between folate intake and colorectal cancer risk by level of alcohol intake.
Few studies have assessed the relationship between vitamin B6
and colorectal cancer risk. In the Nurses' Health Study, plasma vitamin B6
was inversely associated with the risk of colorectal cancer and adenoma (40
). In the Iowa Women's Health Study, higher vitamin B6
intake was not independently associated with the risk of colon cancer but was significantly inversely associated with proximal colon cancer when combined with high folate intake (15
). Several case-control studies reported a lower risk of colorectal cancer associated with higher vitamin B6
). However, two other studies observed no overall associations (28
Our findings that suggest a possible inverse relationship of colorectal cancer risk with intakes of dietary folate and dietary vitamin B6
rather than with total folate and total vitamin B6
are intriguing. Such findings are consistent with the results from a recent meta-analysis of seven cohorts and nine case-control studies on folate intake and colorectal cancer risk, which reported a stronger inverse association for dietary folate than for total folate (42
). However, these findings for folate seem to conflict with the fact that folic acid used in supplements is in the form of monoglutamate, which bypasses deconjugation for intestinal absorption, and is thus more bioavailable than dietary folate (43
). One possible explanation is that dietary nutrient intakes (from foods only) calculated from the food frequency questionnaire may be more likely to reflect participants' long-term intakes than total nutrient intakes (from foods and supplements) as dietary intakes may have been consistent over long periods whereas widespread use of vitamin supplements is relatively recent. Because of cancer's long latent period, it is highly plausible that colorectal cancer may be related to a long-term or remote dietary exposure. In the Nurses' Health Study, a protective effect of multivitamin supplement use on colon cancer risk was mostly seen among users for 15 or more years (11
). Due to a small number of cases, we were unable to evaluate the risk of colorectal cancer in the category of 15 or more years of multivitamin supplement use.
Another possible explanation is that folate and vitamin B6 may reduce the risk of colorectal cancer in women with a diet low in these vitamins. Our finding that an inverse association for dietary folate and dietary vitamin B6 was observed among women not taking these supplements appears to support such an explanation. It is also consistent with an apparent threshold effect observed for dietary folate and dietary vitamin B6 (i.e., low intake increases risk but incremental intake above the threshold level may add minimum benefits). Because vitamin supplements are typically taken in excess of dietary intake, their removal from the analysis would strengthen the association between dietary folate or dietary vitamin B6 intake and the risk of colorectal cancer. An alternative explanation for the present observations, however, is that dietary intake of folate or vitamin B6 may merely serve as a marker for other constituents in foods that are rich in folate or vitamin B6 (such as fiber or other potential protective constituents) or of lifestyle factors related to risk of colorectal cancer. In our analysis, additional controlling for dietary fiber slightly attenuated the associations for dietary folate. A null association between intake of total folate and total vitamin B6 and colorectal cancer risk might also be a result of surveillance bias because of increased use of colonoscopy or sigmoidoscopy procedures among supplement users. However, this explanation is not supported by the unchanged results from the analysis excluding colorectal cancer cases diagnosed within the first two years follow-up in which the use of colonoscopy or sigmoidoscopy procedures was included in multivariable models. In a subgroup analysis of tumor locations, we also observed an increased risk associated with intakes of total folate and total vitamin B6 for distal colon cancer, but not for proximal colon and rectal cancer. However, because we had limited number of cases in this analysis, these findings need to be interpreted with caution.
Although both the Women's Health Study and the Nurses' Health Study consisted of female health professionals, participants in the Women's Health Study were enrolled much later (1992 vs. 1976) and consumed a healthier diet. More than half of follow-up in the Women's Health Study took place after the mandatory fortification of grain products with folic acid in US (44
). Approximately half of participants in the Women's Health Study consumed at least 400 μg/day of total folate (Dietary Reference Intake of folate for adults (45
)) at baseline. In contrast, only 29% participants in the Nurses' Health Study consumed this amount of total folate at baseline (11
). In addition, the level of alcohol intake in the Nurses' health Study (39
) was more than 2 times higher than that in the Women's Health Study. These factors may contribute to the discrepancy in the results from these two studies.
The data from present study support recommendations to improve folate and vitamin B6
intakes from dietary sources for colorectal cancer prevention. However, the null data for multivitamin supplements alone cannot be definitely viewed as suggesting no role for multivitamin supplements in reducing risk, as some other studies have reported an inverse association between multivitamin supplement use and risk of colorectal cancer, especially among long-term users (39
). On the other hand, the null data on use of multivitamin supplements argue against them playing a major role in colorectal cancer prevention.
In summary, the findings from this large prospective cohort of women suggest that higher dietary intake of folate and vitamin B6 may reduce the risk of colorectal cancer in women. However, an alternative explanation is that other factors related to dietary intake of folate and vitamin B6 may account for the inverse associations.