Using a nationally representative sample of adults from the United States, we examined the hypothesis that vitamin D deficiency contributes to the Black-White racial disparity in death from CRC. We found that being Black was associated with higher CRC mortality compared with Whites; adjusting for vitamin D deficiency attenuated this race effect by 40%. The attenuation did not appear to be attributable to a range of potential confounders including those related to SES, health insurance or behavioral risk factors. These findings are consistent with the hypothesis that vitamin D deficiency explains a portion of the observed Black-White disparity in CRC mortality and raises the possibility that vitamin D supplementation might reduce this disparity.
This study adds to a growing body of evidence showing an association between vitamin D and CRC incidence and/or mortality. The adjusted risk of vitamin D on CRC mortality observed in the present study is slightly higher than the risk on CRC incidence derived from meta-analysis (18
), but similar to an effect on mortality observed with a shorter follow-up period of this cohort (43
). Findings of the current study are consistent with prior observational studies, but go beyond prior research to explore the relationship between vitamin D deficiency and CRC disparities by African-American race.
A review of the published literature on the association between vitamin D and CRC reveals a lack of evidence from randomized controlled trials that vitamin D supplementation prevents CRC (44
). Therefore, causality has not been definitively established and chemoprevention has been shown to be effective only for intermediate outcomes. However, the preponderance of evidence points to a link between vitamin D deficiency and CRC. These data include geographic incidence and UV exposure studies, biological mechanism studies, and data from observational studies of serum levels on incidence of adenomas and incidence of CRC with accompanying dose-response relationships.
To summarize these different lines of evidence, prior epidemiologic studies have shown a higher incidence of CRC at higher latitudes and/or greater UV exposure in the US and Asia (45
). However, the study from China only observed effects in women (46
). A study from Norway found no North-South gradient in CRC mortality, but survival was improved among those diagnosed in summer and fall, when serum levels of vitamin were highest (48
More recent studies explain possible mechanisms of vitamin D protecting against colorectal neoplasia. Vitamin D, possibly in combination with calcium intake, appears to promote colorectal epithelial cell differentiation and apoptosis, increase DNA mismatch repair proteins, and reduce oxidative damage and adenoma recurrence (49
). Furthermore, polymorphisms in the vitamin D receptor are associated with adenoma and cancer risk in various studies (55
). Although these data largely come from studies conducted on participants without neoplasms at baseline, it is possible that similar processes accelerate the progression of cancer, potentially affecting both incidence and survival.
In contrast to geographical and mechanistic studies, the current study contributes to a body of research examining associations between serum vitamin D levels and CRC risk. A meta-analysis of serum 25(OH)D and incidence of colonic adenomas showed an inverse, graded response (57
). Gorham et al
conducted a quantitative meta-analysis of nested case-control studies of serum levels of 25(OH)D collected pre-diagnostically and subsequent incidence of CRC (18
). Three of the six studies showed statistically significant associations. A meta-analysis of all six studies showed a significant effect and dose-response with the very lowest levels associated with the highest incidence. A subsequent meta-analysis conducted by different investigators that included eight studies reached similar conclusions (58
). A large nested case-control study from Europe, published after these meta-analyses were conducted, also showed a strong inverse linear relationship between serum 25(OH)D and CRC incidence (17
). In addition, higher vitamin D levels predict improved CRC survival (59
). Consistent with this group of studies, our findings reveal a significant association between low serum levels of 25(OH)D and CRC mortality.
To date, there has been limited attention given to the possible role of vitamin D deficiency in the Black-White disparity in CRC (21
) despite documentation of much higher rates of vitamin D deficiency among Blacks of all ages (10
). The present study suggests that the racial disparity in CRC mortality is explained in part by vitamin D deficiency in the NHANES III cohort of patients. We observed no interaction between race and serum 25(OH) D. Thus, given high rates of Vitamin D deficiency among Blacks in this national sample, and the finding of an overall effect of low levels with CRC deaths, it is not surprising that deficiency among Blacks contributed to the racial disparity in CRC death. This finding is notable. If vitamin D supplementation is shown to reduce CRC, it could have a substantial impact on the racial disparity in CRC mortality.
Important limitations of these findings include sample size, ascertainment of CRC deaths, single measurement of vitamin D, and potential for unmeasured confounding. Consistent with prior studies (29
), lack of insurance remained a significant predictor of CRC death in the final model, yielding a two and half fold increase in risk. However, it was only measured at baseline; subsequent changes in health insurance might have confounded the relationship between race and CRC mortality. Socioeconomic status is a multidimensional construct that arguably includes factors such as community of residence which were not available in these data (60
); residual confounding between race and socioeconomic status is possible. Furthermore, although our initial cohort was fairly large, the relatively small number of CRC deaths reduced our power to detect effects and confidence intervals were wide.
Death certificate data appear reasonably accurate for CRC deaths, but may over-report colon cancer deaths and under-report rectal cancer (61
). Findings from a meta-analysis show effects of vitamin D on both colon and rectal cancers (58
). Thus, this misclassification may be moot. The level of coding of cancer permitted in public data may have included anal cancer. The pathophysiology of anal cancer is fundamentally different than that for CRC, but likely had negligible effect on our findings given its very low incidence (62
Although we measured vitamin D at a single point in time, prospective studies show moderate correlations (0.7) over time (59
). Any change in levels would likely bias results towards the null due to measurement error. Last, although we controlled for multiple factors, confounding cannot be fully excluded in observational studies. Previous cancer protective effects observed for various nutrients have failed to hold up in randomized controlled trials and in some cases, for example beta carotene for smokers, has been associated with increased risk (63
In conclusion, these findings add to a growing literature on the association between vitamin D and CRC (58
), and provide the first direct evidence that high rates of vitamin D deficiency among Blacks may account for some of the race disparity in CRC deaths. These findings underscore the need for randomized controlled trials such as the Vital Study (64
), to assess whether supplementation with much higher doses than currently recommended will not only reduce deaths from CRC in general, but also reduce the Black-White racial disparity in the second leading cause of cancer related death in the United States.