In this colonoscopy-based case-control study we observed the suggestion of an inverse association between plasma 25(OH)D concentration and colorectal adenomas, but not hyperplastic polyps. When we restricted analysis to participants who reported no previous diagnoses of polyps, the inverse association became stronger for adenomas. These results might be expected if previous polyps indicate a predisposition to polyp formation that attenuates an inverse relationship between vitamin D and adenomas. In contrast, restriction in this manner had less impact on the estimate of the association between hyperplastic polyps and 25(OH)D.
To our knowledge, this is the first study to examine the association of circulating vitamin D metabolites with both colorectal hyperplastic polyps and adenomas in the same population. Recent meta-analyses (17
) of previous studies (12
) have supported an inverse relationship between circulating vitamin D metabolites and first occurrence of adenomas; a similar association has been observed for frank colorectal cancer (18
). Vitamin D has not been widely studied as a risk factor for hyperplastic polyps; the only two studies of which we are aware examining crude dietary intake of vitamin D, without direct measurement of circulating vitamin D metabolites, found no association (25
This study has several strengths, including the performance of colonoscopy on all participants, so that we can be confident that controls were, in fact, polyp-free at the time of this study. Secondly, blood sampling and questionnaire responses were obtained prior to colonoscopy and resulting diagnosis, so that participation rates, recall, and 25(OH)D were unlikely to be affected by case-control status. We were able to identify both adenomas and hyperplastic polyps in the same population, and our results reproduce the well-characterized relation between 25(OH)D and adenoma (17
), increasing our confidence in the findings.
Another important strength is the direct assessment of circulating concentration of the salient vitamin D metabolite, 25(OH)D, with a mass spectrometry-based method that has high sensitivity and specificity for 25(OH)D (28
) and is considered the “gold-standard” for clinical assessment of 25(OH)D (30
). This method can also distinguish 25(OH)D2
). Vitamin D3
is produced in the human body as a result of exposure to UV radiation, is the most common form of vitamin D in supplements, is found in foods such as fish, and is most commonly added to milk (8
). Vitamin D2
is a component of some supplements, for example, those obtained by physician prescription in the US, and may be present in small amounts in some foods such as mushrooms (31
). We observed that 25(OH)D2
levels above 5.1 ng/mL were only found in participants who indicated taking supplements, and that 25(OH)D3
concentrations increased with supplement use and higher levels of physical activity (data not shown). When 25(OH)D2
were separately accounted for in a single regression model, 25(OH)D3
was inversely associated with adenomas but not hyperplastic polyps, while 25(OH)D2
was not associated with either polyp. However, the restricted range of 25(OH)D2
concentrations hampered our ability to conclude that only 25(OH)D3
, and not 25(OH)D2
, is likely to be inversely associated with adenoma risk.
In a sub-analysis, we divided each case group between two subgroups according to the site of polyp(s). The suggested inverse association between 25(OH)D and adenoma was stronger for adenomas in the distal colon and rectum than for proximal adenomas. Many previous studies of 25(OH)D and adenomas have been sigmoidoscopy-based, and therefore, unable to examine in detail differences in association with respect to lesion location throughout the colorectum (12
). The results of other studies that did examine lesion site have been mixed. A stronger association of 25(OH)D with distal lesions was not observed in at least two studies (13
), but was reported in another study based on dietary intake of vitamin D (35
The limitations of this study include its cross-sectional nature. We assayed 25(OH)D in plasma collected at the time of colonoscopy and assessed its relationship with polyps identified at the same colonoscopy. Although there is little reason to suspect that the presence of polyps alters circulating 25(OH)D, we cannot know whether measured 25(OH)D reflects 25(OH)D levels prior to polyp formation. However, recent longitudinal studies of 25(OH)D levels support the validity of a single 25(OH)D measurement as a marker of long-term 25(OH)D status (36
The study sample comprised largely non-Hispanic whites, which may limit the application of these results to more diverse populations. We observed that 25(OH)D concentrations were lower among non-whites in this study sample, consistent with nationally representative samples (38
). Although vitamin D receptor polymorphisms might vary across ethnicities (39
), the functional relevance of these polymorphisms in relation to 25(OH)D and colorectal polyps remains uncertain.
In addition, we were unable to assess intake of calcium, possibly an important co-factor with 25(OH)D in colorectal polyp development (40
). Therefore, some of the association we observe between vitamin D and colorectal adenomas might be due to differences in calcium levels rather than vitamin D levels. However, vitamin D increases absorption of ingested calcium (32
), an action that might mediate part of the association between 25(OH)D and adenoma or hyperplastic polyps (40
). Therefore, complete adjustment for calcium status may be inappropriate when estimating the association between 25(OH)D and polyps, and our inability to assess calcium intake is unlikely to substantially impact the interpretation of our results.
Notably, adjustment for reported physical activity level and current use of multivitamins, vitamin D supplements, or calcium supplements only weakly attenuated the association between circulating 25(OH)D and adenoma (). Adjustment for activity and supplement use resulted in decreases of the ORs between 25(OH)D and hyperplastic polyps, particularly among participants without a history of prior polyps. This was mainly attributable to adjustment for supplement use, and only a small portion was related to adjustment for physical activity. This suggests that although physical activity and supplement use are both sources of 25(OH)D, only supplement use is a potentially important confounder of the association between 25(OH)D and hyperplastic polyps in this study sample, after adjustment for the other variables in our base model. Because of limited data we were unable to more fully adjust for supplement use, for example, by including dose information. Although such additional adjustment might further attenuate the observed association between 25(OH)D and hyperplastic polyps, it is unlikely to fully account for the observed qualitative differences in comparison to the association between 25(OH)D and adenomas.
Emerging molecular evidence suggests that a subset of colorectal cancers displaying high microsatellite instability and CpG-island methylation may progress from hyperplastic polyps along the “serrated polyp” pathway (3
), distinct from the more common adenoma-cancer pathway (1
). Epidemiologic studies, however, have generally found few differences between risk factors for hyperplastic polyps and adenomas; the most consistently observed differences are a stronger association between cigarette smoking and hyperplastic polyps than adenomas, and a younger mean age of individuals with hyperplastic polyps (25
The results of this study provide preliminary evidence that vitamin D status may be another risk factor that differs between adenomas and hyperplastic polyps, suggesting that vitamin D and the molecular processes regulated by the vitamin D receptor might provide some insights into etiologic differences. In particular, the regulatory actions of the vitamin D receptor on the Wnt
/β-catenin signaling pathway, which is critical to adenoma development, has been suggested to mediate the apparent protective effect of vitamin D against adenomas and colorectal cancer (47
). Although speculative, our results are consistent with a model in which the Wnt
/β-catenin pathway is less relevant to the development of hyperplastic polyps, and perhaps also to the progression of hyperplastic polyps to sessile serrated adenomas and colorectal cancer.