In this large population-based case–control study, each antioxidant nutrient was associated with reduced distal CRC risk in whites, and there was an inverse trend in risk for selenium intake in African Americans. Inverse associations with DNA methylation-related nutrients were only observed in whites, and there were significant positive linear trends for total folate and total vitamin B6 in African Americans.
There were notable differences in mean nutrient intakes between whites and African Americans. In general, African American controls reported lower mean intakes than white controls, primarily due to the greater contribution to intake from dietary supplements in whites. The prevalence of any dietary supplement use in the last 12 months among our control population was 72% in whites and 53% in African Americans. It has been estimated that approximately 50–70% of non-institutionalized US adults take dietary supplements in the form of multivitamin/mineral or singlenutrient supplements [17
], and Radimer et al. [17
] also noted that supplement use patterns differ by race. Therefore, it is necessary to collect detailed information on supplement use when assessing the effect of micronutrients on disease risk, especially in racially diverse populations.
Findings in this present study for whites are consistent with the hypotheses that dietary antioxidants may reduce the risk of distal CRC. Our results are in agreement with other observational studies reporting significant inverse associations for dietary antioxidant intake and colon [32
] and rectal cancer [33
]. Kune and colleagues reported colon and rectal cancer risk reductions for high intakes of vitamin C, vitamin E, and selenium [33
], and elevated risk of rectal cancer has been observed for low vitamin E intakes in women [36
]. On the contrary, there was no effect of vitamin E on colon cancer in the Women’s Health Study clinical trial [37
], and a large population-based case–control study reported no association between β
-carotene intake and proximal or distal colon cancer [38
]. Most of the current evidence has been limited to non-African American populations; however, in a previous case–control study Satia-Abouta et al. noted significant inverse associations with colon cancer for high intakes of β
-carotene, vitamin C, and vitamin E in African Americans [34
]. We did not observe any statistically significant risk estimates for antioxidant nutrients in African Americans in the present study.
We also found intakes of DNA methylation-related nutrients to be associated with reduced risk of distal CRC in whites. Results are conflicting regarding the effect of folate on CRC development. In a recent report of the Netherlands Cohort Study, the authors did not find folate to be significantly associated with CRC risk in men or women [39
]. Null findings have also been reported for folate and colon cancer [34
]. The most recent report from the World Cancer Research Fund/American Institute for Cancer Research indicated that there is only limited suggestive evidence that folate reduces the risk of CRC [43
]. Epidemiologic studies of vitamin B6 and B12 are limited in comparison with studies on folate intake. The present study is in agreement with findings from an Australian case–control study in which there was a statistically significant lower risk of colon and rectal cancer for the highest categories of vitamin B6 and B12 intake [33
]. On the other hand, two large prospective studies observed an elevated risk of rectal cancer in women for high intake of vitamin B6 [39
]. These discrepant findings may be due to inherent biases in case–control studies, the method of dietary assessment, or variation in intakes of these micronutrients. We did not observe interactions with alcohol for any of these DNA methylation-related nutrients, although alcohol is a known to interact with these nutrients [44
]. This may be because the average alcohol intake in our study population (8 g/day) was much lower than the level at which alcohol intake has been shown to be associated with elevated CRC risk (≥30 g/day) [19
The reasons why the associations between micronutrients and distal CRC differ for whites and African Americans are not totally clear. Surprisingly, the odds ratios for high total intakes of vitamin C and all DNA methylation-related nutrients suggested elevated risk of distal CRC in African Americans, although they were not significant. This direct association may be due to the source of these nutrients; however, after controlling for fruit and vegetable consumption there was still a non-significant positive association with risk. Due to our small sample of African Americans, we may have missed other statistically significant associations, and this small sample size may also have led to unstable estimates. We did, however, observe a significant inverse trend for selenium, and positive trends for total folate and total vitamin B6. Results from other epidemiologic studies with adequate African American representation are needed to confirm (or dispute) these findings.
It is interesting to note that for all DNA methylation-related nutrients and vitamin E in whites, the risk reduction was greater for intake from food sources only compared to total intake (food plus supplements). Other studies have reported null effects of supplement use on colorectal cancer [45
] and adenomas [47
]. For example, compared to the placebo, 1 mg/day of folic acid did not reduce the risk of colorectal adenomas, the precursor to colon and rectal cancer, and actually increased the risk of advanced adenomas in the Aspirin/Folate Polyp Prevention Study [48
]. There are several possible explanations for these findings. One reason may relate to the dual effect of folate, depending on dosage and time of exposure. While adequate folate intake may suppress tumor development, excessive intake may not offer additional benefit or even enhance carcinogenesis, especially when there are pre-existing lesions [49
]. These disparate findings may also reflect the different chemical structures and biological pathways of natural folate and synthetic folic acid. Folic acid is more bioavailable and therefore more readily absorbed than natural folate found in food [50
]. However, high circulating levels of unmetabolized folic acid may reduce the immune response against carcinogenic cells by reducing the amount of natural killer cells [50
]. When considering intake from foods versus supplements, it is important to note that foods can contain the synthetic form of the nutrient due to fortification. For example, mandatory fortification in the United States resulted in an average total folate intake of approximately 400 μg/day among supplement non-users, with only about 200 μg/day being naturally occurring folate and 200 μg/day being folic acid in fortified foods [51
Clinical trials have also found no evidence for associations of vitamin C, vitamin E, or β
-carotene with reduced risk of CRC [45
]. One trial reported a significant inverse association of vitamin E supplementation and colon cancer risk, but there was no statistically significant association with rectal cancer [46
]. Therefore, these supplements may have different effects on proximal and distal sites in the colon. Also, at high concentrations, vitamins C and E may exert pro-oxidant effects, and thereby promote oxidative DNA damage. Our study results suggest that nutrient intake from dietary supplements may not help reduce distal CRC risk, and that intake from food sources alone may be more relevant for risk reduction. This could be because supplement use may only benefit those with suboptimal nutrient intakes, while providing no benefit for those with adequate intakes. In our study, the mean intake of these micronutrients from food alone in whites and African Americans was above the daily recommended intakes [53
]. In addition, other compounds of natural foods such as phytochemicals and fiber may be chemopreventive and act in synergy with these nutrients to reduce distal CRC risk, and it is likely that past and long-term supplement use may be associated with risk as opposed to recent use. Currently, the overall evidence for recommending supplements for CRC is weak [54
A major strength of this study was our large sample size, especially for a study of distal colorectal cancer. This allowed us to observe associations that would be undetectable in studies with fewer participants. All data were collected in-person by trained nurse-interviewers, thereby minimizing the potential for misclassification. We collected detailed information on dietary supplement use to include in our assessment of total nutrient intake. Our study is among the first reports of micronutrient intake and distal CRC risk in African Americans.
There are some limitations worth noting. Our study was subject to potential biases in case–control studies such as recall bias. It is possible that there was differential recall between cases and controls. Differential response rates between cases and controls, as well as between whites and African Americans, could have biased our results. There was also the potential of measurement error; however, the diet history questionnaire has been validated [29
], although not in African American populations. We cannot exclude the possibility of chance findings due to multiple testing and the possibility of residual confounding.
In summary, the present findings add to the evidence that dietary antioxidants (vitamin C, vitamin E, β-carotene, selenium) and DNA methylation-related nutrients (folate, vitamin B6, vitamin B12) are associated with lower risk of distal colorectal cancer in whites. Our results also support the hypotheses of mechanisms by which these nutrients may play a role in preventing colorectal cancer. Our findings suggest that the associations between these nutrients and distal colorectal cancer may differ between whites and African Americans. This stresses the importance of examining these associations by race in large racially diverse samples. Furthermore, intakes from dietary supplements appeared to attenuate the risk reduction in whites for some nutrients, suggesting that optimal intakes of these nutrients from food sources alone may be sufficient to lower risk of distal colorectal cancer.