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Departments of Epidemiology [E. A. P., S. E. H., G. A. C., D. J. H., E. G.] and Nutrition [E. A. P., D. J. H., E. G.], Harvard School of Public Health, Boston, Massachussetts 02115; Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham & Women’s Hospital [S. E. H., G. A. C., D. J. H., F. E. S., E. G.], Boston, Massachussetts 02115; and Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina 29425 [B. W. H.]
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The immediate precursor of 1,25(OH)2D is 25(OH)D, which is formed in the liver from cholecalciferol (vitamin D) and which is considered to be the best indicator of nutritional vitamin D status (11) . The major dietary sources of vitamin D are fish, eggs, butter, fortified milk products, and multivitamins and specific vitamin D supplements. The conversion of 7-dehydrocholesterol to vitamin D in the skin by UV light contributes to vitamin D stores (12) . Production of 1,25(OH)2D, which is present in plasma at a concentration of about 30 pg/ml, is tightly regulated (13) and typically does not substantially change with alterations in dietary vitamin D intake and sunlight exposure. Conversely, 25(OH)D level is not tightly homeostatically controlled in adults (14) and, thus, reflects both dietary and sunlight sources of vitamin D. 25(OH)D circulates bound to vitamin D-binding protein at a concentration of 10–50 ng/ml (13) . The half-lives of 25(OH)D and 1,25(OH)2D are 3 weeks and 4–6 h, respectively (15) .
Epidemiological studies of dietary intake of vitamin D and colorectal cancer or adenoma have not considered the vitamin D contribution from sunlight. Three studies (16, 17, 18) , two of which were conducted in the same cohort (16 , 17) , have evaluated the relationship of blood levels of vitamin D metabolites and colorectal cancer. Two (16 , 18) , but not the third (17) , showed an inverse relationship for 25(OH)D. The studies (17 , 18) that measured 1,25(OH)2D concentration noted no relationship with colorectal cancer.
In this report, we present our findings from a case-control study nested in the prospective Nurses’ Health Study on the relationship of distal colorectal adenoma to plasma 25(OH)D and 1,25(OH)2D. This analysis thus integrates dietary and sunlight sources of vitamin D.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Selection of Cases and Controls.
Cases and controls were chosen from among women who supplied a blood
sample in 1989–1991, had a sigmoidoscopy or colonoscopy after
providing a blood sample (1989–1996), and were free from diagnosed
cancer (except nonmelanoma skin cancer) and polyps before endoscopy.
Newly diagnosed polyps (in individuals who before the date of blood
draw never had a polyp diagnosed) were reported on the 1990, 1992,
1994, or 1996 questionnaires. These polyps were confirmed to be
adenomatous by review of histopathological reports and were classified
by location (proximal or distal colon, or rectum), size (<1 cm, 
1
cm), and histology (villous, tubulovillous, tubular) by study
investigators blinded to exposure information. Hyperplastic and
other nonadenomatous polyps were excluded. We were able to obtain
medical records for 93% of the women reporting a polyp diagnosis.
Because most of the endoscopies were limited to the sigmoid colon and, thus, could not detect proximal colon adenomas, we included as cases only women with adenomas of the distal colon and rectum. Because endoscopied controls who had a sigmoidoscopy may also have had an undetected proximal adenoma, we included women with detected proximal colon adenomas in the pool of individuals who were eligible to be selected as a control. Controls were matched to cases based on endoscopy during the same 2-year period, year of birth, indication(s) for endoscopy (58% gastrointestinal symptoms, 48% routine screening, 19% because of family history), time period of first or most recent endoscopy excluding the one in the current time period, and date of blood draw. For all of the cases, a matched control was successfully identified. A total of 326 matched pairs were included in the analysis. Of the cases, 36.8% and of the controls, 31.9% had had a negative endoscopy prior to the blood collection period, with 50% of those endoscopies having taken place 10 or more years before blood draw.
Plasma 1,25(OH)2D and 25(OH)D Assays.
Plasma 1,25(OH)2D and 25(OH)D
concentrations were determined by RIA as described previously
(11
, 20)
. The mean intrapair coefficients of variation
calculated from blinded quality control samples were 9.9% for
1,25(OH)2D and 7.5% for 25(OH)D.
Assessment of Other Factors.
Mean values for anthropometric, dietary, and other covariates were
computed from the 1980-through-1990 questionnaires, including body mass
index (weight in kg/height in m2), physical
activity [metabolic equivalent tasks (MET)-h/week], regular
aspirin use (2+ days/week), cigarette smoking (pack-years), alcohol
consumption (g/day), red meat intake (servings/day), and dietary intake
of methionine (g/day) adjusted for total energy intake by residual
analysis (21)
. Mean values were used to obtain measures of
consistent exposure over time to these factors. We also assessed
current (1990) use of postmenopausal hormones, and vitamin D and
calcium-containing multivitamins and supplements. In this cohort,
current postmenopausal hormone use rather than past use is more
strongly related to risk of colorectal cancer and adenoma
(22)
, and the relatively short half-lives of the two
vitamin D metabolites suggest that plasma concentrations would reflect
current vitamin D and calcium intakes. We used 1980 energy-adjusted
dietary intake of folate (µg/day) plus intake from multivitamins and
supplements to represent past exposure level; only long-term use of
multivitamins and supplements for more than 15 years appears to be
inversely associated with risk of colorectal neoplasia in this cohort
(23)
and intake of folic acid has increased in the recent
years. We obtained mean daily solar UV irradiation (24)
for the UV monitoring station closest to the postal code of each
woman’s residence in 1990.
Data Analysis.
We estimated ORs and corresponding 95% CIs for the relationship
between plasma 1,25(OH)2D and 25(OH)D and
adenomatous polyps of the distal colon and rectum from conditional
logistic regression models with the vitamin D metabolites entered in
quartiles with cutpoints based on the distribution among controls. We
also estimated the OR for having a plasma
1,25(OH)2D level below 26.0 pg/ml
(25)
or for having a plasma 25(OH)D level below 15 ng/ml
(26)
, levels typically considered to be clinically below
normal. We considered distal colorectal adenoma, and separately distal
colon adenoma, as well as adenoma size (small, <1 cm; large, 1 cm)
and potential for progression to colorectal cancer (lower risk: small
and tubular histology; higher risk: large or villous/tubulovillous
histology). To adjust for possible confounding, we entered body mass
index, physical activity, regular aspirin use, cigarette pack-years
smoked, and intake of alcohol, red meat, folate, and methionine, and
current postmenopausal hormone use as covariates in conditional
logistic regression models. Covariates chosen for inclusion in the
multivariate models were based on a priori hypotheses for
colorectal cancer and adenoma risk factors. To increase efficiency, we
modeled all of the covariates as continuous terms, except aspirin and
postmenopausal hormone use, which we modeled as binary. We tested for
trend by entering continuous terms for 1,25(OH)2D
or 25(OH)D into the conditional logistic regression model. We used
stratified analysis to examine whether the association between distal
colorectal adenoma and clinically low plasma
1,25(OH)2D level varied by use of vitamin D
supplements in 1990 (binary), consistent total vitamin D intake (within
1 decile in 1980 and 1990, binary) or calcium supplement use in 1990
(binary), mean daily solar UV irradiation (cutpoint at median, binary),
or season of blood draw (winter/early spring: January, February, March,
April; summer/early fall: July, August, September, October; late
spring/late fall: May, June, November, December). To test for
statistical multiplicative interaction, the product of clinically low
1,25(OH)2D and each of the above factors
expressed as a continuous term (season as an ordinal variable) was
entered along with each covariate into the conditional logistic
regression model; we evaluated the statistical significance of the
interaction terms by the Wald test. All of the analyses were done in
SAS version 6.12 (SAS Institute, Cary, NC).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Cases tended to be less likely to use aspirin and postmenopausal
hormones regularly and to be more likely to smoke more (Table 1)
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. However,
women whose plasma concentration was below the typical lower cutpoint
for clinically normal, 1,25(OH)2D level of 26.0
pg/ml (cases, n = 90; controls, n =
69), had an increased risk of distal colorectal adenoma of 1.58 (95%
CI, 1.03–2.40) after controlling for the dietary and life-style
covariates. The OR for distal colorectal adenoma among women whose
25(OH)D level was below 15 ng/ml (cases, n = 42,
controls, n = 33) was 1.29 (95% CI, 0.75–2.20). Only
10 cases and 8 controls had low levels of both vitamin D metabolites.
Compared with the lowest 1,25(OH)2D quartile,
women in the second (OR, 0.64), third (OR, 0.80), and upper (OR, 0.71)
quartiles appeared to have a slight, but not significant, downward
trend (P-trend, 0.4) in multivariate models (Table 2)
. For plasma 25(OH)D level, women in the second (OR, 0.64) and third
(OR, 0.58) quartiles were at significantly lower risk of distal
colorectal adenoma compared with the first quartile. There was no
difference in risk in the top quartile (OR, 1.04; Table 2
). The
associations were essentially unchanged before and after controlling
for body mass index, physical activity, aspirin use, cigarette
pack-years smoked, alcohol consumption, intake of red meat, folate, and
methionine, and postmenopausal hormone use (Table 2)
. The associations
also were similar before and after mutually controlling for
1,25(OH)2D and 25(OH)D (not shown). Adjusting for
intake of vitamin D and calcium overall and from dairy and nondairy
sources, or adjusting for milk consumption did not attenuate these
associations. There was no association between the ratio of
1,25(OH)2D:25(OH)D and distal colorectal adenoma
(ORs for quartiles 1–4: 1.00, 0.83, 0.90, and 0.91;
P-trend, 0.8).
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Because season of the year in which blood was collected likely influences levels of 25(OH)D, and possibly 1,25(OH)2D in individuals who have low circulating levels of 25(OH)D, we repeated the multivariable analysis using separate cutpoints for quartiles by season of blood collection. The observed associations between distal colorectal adenoma and 1,25(OH)2D (ORs for quartiles 1–4: 1.00, 0.59, 0.72, 0.68) and 25(OH)D (ORs for quartiles 1–4: 1.00, 0.51, 0.71, 0.94) were comparable with the overall findings.
There was no association between rectal adenoma and
1,25(OH)2D level, although the U-shaped
relationship for 25(OH)D that was seen overall was also present for
rectal adenoma (Table 3)
. As would be expected, restricting the cases to those of the distal
colon (80% of cases) resulted in a modest increase in strength of the
inverse association for the top three quartiles (Table 3)
. The OR
comparing women below the typical normal cutpoint for
1,25(OH)2D level increased to 1.86 (95% CI,
1.16–2.98) for distal colon adenoma (cases, n = 75;
controls, n = 53). Women whose 25(OH)D level was below
the typical normal cutpoint were not at increased risk of distal colon
adenoma (OR, 1.12; 95% CI, 0.62–2.02). The U-shaped relationship for
25(OH)D level was observed irrespective of adenoma size (large: 1 cm,
small: <1 cm) or histology (villous/tubulovillous, tubular). The lower
risk of adenoma among women in the top three quartiles of
1,25(OH)2D was stronger for larger or
villous/tubulovillous adenoma than for small and tubular adenoma (Table 3)
. For women whose plasma 1,25(OH)2D level was
below 26.0 pg/ml, the OR for large or villous/tubulovillous was 1.62
(95% CI, 0.87–3.03) and for small and tubular adenoma was 1.45 (95%
CI, 0.84–2.50).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Because risk factors for cancer and adenoma have been seen to differ
between the colon and rectum [e.g., physical activity and
adenoma (27)
], we presented the results combined, and
separately for the rectum and distal colon. The reduced risk of adenoma
associated with higher plasma 1,25(OH)2D was
apparent for the distal colon, but not for the rectum, although the
U-shaped relationship of 25(OH)D with adenoma was present for both
sites. Because the progression to malignancy is thought to proceed from
small to large adenoma and with increasingly less differentiated
histology, and because vitamin D metabolites may play a role in control
over cellular proliferation and differentiation, we also explored
whether the relationship of plasma levels of
1,25(OH)2D and 25(OH)D with distal
colorectal adenoma differed by the combination of size and histology. A
reduced risk associated with higher 1,25(OH)2D
levels was present for adenomas that were large (1 cm) or
villous/tubulovillous, but not small and tubular. This finding possibly
suggests that 1,25(OH)2D may not act on the
development of adenoma but may play a role in the control of
progression to larger and more dysplastic adenoma phenotypes. The
U-shaped relationship between 25(OH)D and adenoma was present for both
of the size/histology combinations.
We used plasma concentration of two vitamin D metabolites as measures of vitamin D nutritional [25(OH)D] and hormonal [1,25(OH)2D] status. 1,25(OH)2D is generated in the proximal renal tubules of the kidney by hydroxylation of 25(OH)D and is regulated in part by parathyroid hormone in response to low plasma calcium (12) . 25(OH)D is generated from hydroxylation by liver microsomal mixed function oxidase of cholecalciferol ingested in the diet or obtained as a skin photoproduct of 7-dehydrocholesterol (12) . Unlike 1,25(OH)2D, the production of 25(OH)D is not tightly regulated in adults.
Like other steroid hormones, 1,25(OH)2D transactivates the transcription of target genes, of which one result is the stimulation of calcium transport across the small intestinal epithelium (12) . Whether related to its effect on calcium or independent of it, 1,25(OH)2D has been shown: (a) to inhibit proliferation and to induce differentiation of human colon cancer cell lines (5 , 6) as well as other malignant tumor lines (28 , 29) ; (b) to suppress growth of solid tumor xenografts in vivo (30) ; and (c) to reduce the incidence of carcinogen-induced colon tumors in rodents (31, 32, 33) . Receptors for 1,25(OH)2D have been detected in colon cancer cell lines (6 , 34) , and expression of the receptor is greater in well-differentiated cell lines than in those that are less well differentiated (5 , 35 , 36) .
Because colorectal cancer mortality rates were higher in areas of the United States with the lowest exposure to sunlight, Garland and Garland (37) proposed in 1980 that vitamin D may play a preventive role in this cancer. Three additional ecological studies (38, 39, 40) that have evaluated the solar radiation and colorectal cancer relationship supported this hypothesis. Several cohort studies (1, 2, 3, 4) and case-control studies (41, 42, 43, 44, 45, 46) have evaluated the relationship between dietary intake of vitamin D and colorectal cancer. Some of these studies suggested weak to moderate inverse associations (1, 2, 3, 4 , 41 , 42 , 45) , ranging from a RR for colorectal cancer of 0.88, comparing extreme quintiles of combined intake of vitamin D from the diet and supplements in the Nurses’ Health Study of 501 cases among 89,448 women followed for twelve years (1) , to a RR of colorectal cancer of 0.5, comparing extreme quartiles of vitamin D intake (P-trend < 0.05) in the Western Electric study of 47 cases among 1,924 men followed for 19 years (4) .
Three studies have evaluated the relationship of plasma levels of
vitamin D metabolites and colorectal cancer, two of which were
conducted in the Washington County, Maryland cohort (16
, 17) , and the other nested in the Finnish 
-Tocopherol,
ß-Carotene Cancer Prevention Study (18)
. The study by
Garland et al. (16)
, which included 34 cases
with a range from several months to 8 years between blood donation and
colorectal cancer diagnosis and 67 controls, showed an inverse
relationship between 25(OH)D and colorectal cancer, although in the
highest quintile, the inverse association was not as strong as in the
middle three quintiles. In contrast, the study by Braun et
al. (17)
, which included 57 cases with 10–17 years
between donation and diagnosis and 114 controls, and which measured
both 25(OH)D and 1,25(OH)2D, did not detect any
notable relationships. In the Finnish study, no relationship was
observed between serum 1,25(OH)2D concentration
and colorectal cancer among the 91 colon and 55 rectal cancer cases and
290 controls, but an inverse relation was suggested for 25(OH)D level,
particularly for the rectum (18)
.
One case-control study (44) and two cohort studies (10) have reported on the relationship between vitamin D intake and colorectal adenoma. Findings were not consistent across gender or on the location within the colon. In the case-control study consisting of 154 small and 208 large adenoma cases, an inverse association with vitamin D intake was seen for small adenomas in women (extreme quintiles: OR, 0.4; P-trend, 0.04; Ref. 44 ), whereas in the cohort studies, an inverse relationship was seen only for rectal adenomas in women (extreme quintiles: RR, 0.30; P-trend, 0.005; Ref. 10 ).
There are several issues in the current analysis that require consideration. We cannot exclude the possibility that the biologically relevant vitamin D exposure to the target tissue is misclassified when using either of the plasma vitamin D metabolites as markers. Measurement error in a woman’s typical circulating vitamin D metabolite concentrations may have occurred because we measured these levels at a single point in time. However, the extent of measurement error in the plasma levels is unlikely to differ between the cases and controls because of the study design and assay controls. Evidence for some attenuation of the 1,25(OH)2D and adenoma relationship attributable to measurement error comes from the observation of a stronger increased risk of adenoma for clinically low plasma 1,25(OH)2D and a stronger trend of decreasing risk of adenoma with increasing levels of 1,25(OH)2D among those with consistent vitamin D intake from 1980 to 1990. Because plasma 25(OH)D level, as a precursor for 1,25(OH)2D, and low plasma 1,25(OH)2D level in part, may be determined by dietary and supplemental intake of vitamin D, those with consistent vitamin D intake would more likely have vitamin D metabolite concentrations measured in blood collected in 1989/1990 that are representative of circulating levels in the previous 10 years. In any case, this earlier period may be more relevant for adenoma development and progression in women whose polyps were detected between 1989 and 1996.
We used 26 pg/ml as a definition of clinically low 1,25(OH)2D, which we selected a priori. Nearly 28% of the cases and 21% of the controls had plasma 1,25(OH)2D concentrations that measured below 26 pg/ml When we reanalyzed the data using a second arbitrary cutpoint dependent on the distribution of 1,25(OH)2D among the controls, below the bottom quartile of 1,25(OH)2D (<26.9 pg/ml), the OR for distal colorectal adenoma was 1.41 (95% CI, 0.95–2.09) and the OR for distal colon adenoma was 1.64 (95% CI, 1.05–2.56). Whether the women in this nested case-control study who have 1,25(OH)2D levels in the bottom quartile or <26.9 pg/ml are truly deficient is unknown. Estimated mean solar UV irradiation (P = 0.05) was significantly lower among the controls with low 1,25(OH)2D than among the controls with normal range levels. However, current age or current or 1980–1990 average intake of vitamin D, calcium, or phosphorus, was not associated with 1,25(OH)2D level.
Among users of multivitamins, intake of vitamin D may be confounded by folic acid in the multivitamins. Folic acid is inversely associated with colorectal cancer and adenoma in this cohort (47) . We, therefore, stratified the analysis by users of multivitamins and supplements containing vitamin D. Among nonusers, who are thus less likely to be users of multivitamin and supplements containing folate, the relationship between plasma 1,25(OH)2D and 25(OH)D was similar to the overall relationships.
We also examined whether the direct association of low 1,25(OH)2D with adenoma varied by calcium-supplement use, because the use of such a supplement during the same period as the blood draw could result in a down-regulation of 1,25(OH)2D level. However, no difference in risk of adenoma associated with low 1,25(OH)2D was observed between users and nonusers of supplemental calcium. No variation in the risk of adenoma with clinically low 1,25(OH)2D was observed in regard either to the estimated residential UV irradiation levels at the time of blood draw or to the season of the year, which both may be determinants of plasma 25(OH)D level and low 1,25(OH)2D concentration.
Although blood was obtained before the detection of adenoma, because we did not require that participants undergo endoscopy at the time of blood draw to ensure that they were polyp-free, it is unknown what proportion of these adenomas were present at the time of blood draw. For adenomas that developed before blood was provided in 1989–1991, earlier plasma vitamin D metabolite concentrations may be more relevant. Nevertheless, when we limited the analysis to cases diagnosed more than 2 years after blood was obtained, the results were comparable with those observed overall.
To minimize confounding, we controlled for suspected colorectal
neoplasia risk factors. The cases and controls in this sample of women
in the Nurses’ Health Study did not differ on some of these suspected
colorectal neoplasia risk factors that were observed previously in the
entire cohort (Table 1)
. A possible explanation for the lack of a
difference is that these factors are more strongly associated with
large adenoma (1 cm) and cancer rather than with adenoma
overall. To increase efficiency, particularly for subgroup analyses, we
adjusted for the suspected colorectal neoplasia risk factors using
continuous or binary terms. Although residual confounding is possible
because of inadequate expression of these factors in the models, we
believe that these factors are unlikely to be strongly related to
vitamin D metabolite concentrations, and, thus, the degree of residual
confounding is likely small.
We conclude that women who have low levels of circulating 1,25(OH)2D concentrations may be at higher risk of distal colorectal adenoma. Nevertheless, additional studies in populations with differing ranges of circulating vitamin D metabolites along with measurement of plasma levels at several points in time are warranted.
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Acknowledgments |
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Footnotes |
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1 Supported by NIH Grants CA55075, CA40356, and
CA49449. 
2 To whom requests for reprints should be
addressed, at Department of Epidemiology, Johns Hopkins School of
Hygiene and Public Health, 615 North Wolfe Street, Room E6143,
Baltimore, Maryland 21205.
3 The abbreviations used are:
1,25(OH)2D, 1,25-dihydroxyvitamin D; 25(OH)D,
25-hydroxyvitamin D; OR, odds ratio; CI, confidence interval; RR,
relative risk.
Received 5/ 7/98; revised 7/26/00; accepted 8/14/00.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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,25-dihydroxyvitamin D is loosely regulated in normal children. J. Clin. Investig., 68: 1374-1377, 1981.
,25-dihydroxyvitamin D3 induces differentiation of human myeloid leukemia cells. Biochem. Biophys. Res. Commun., 102: 937-943, 1981.[Medline]
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P. R. Holt, N. Arber, B. Halmos, K. Forde, H. Kissileff, K. A. McGlynn, S. F. Moss, K. Fan, K. Yang, and M. Lipkin Colonic Epithelial Cell Proliferation Decreases with Increasing Levels of Serum 25-Hydroxy Vitamin D Cancer Epidemiol. Biomarkers Prev., January 1, 2002; 11(1): 113 - 119. [Abstract] [Full Text]
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U. Peters, K. A. McGlynn, N. Chatterjee, E. Gunter, M. Garcia-Closas, N. Rothman, and R. Sinha Vitamin D, Calcium, and Vitamin D Receptor Polymorphism in Colorectal Adenomas Cancer Epidemiol. Biomarkers Prev., December 1, 2001; 10(12): 1267 - 1274. [Abstract] [Full Text] [PDF]
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E. Kallay, P. Pietschmann, S. Toyokuni, E. Bajna, P. Hahn, K. Mazzucco, C. Bieglmayer, S. Kato, and H. S. Cross Characterization of a vitamin D receptor knockout mouse as a model of colorectal hyperproliferation and DNA damage Carcinogenesis, September 1, 2001; 22(9): 1429 - 1435. [Abstract] [Full Text] [PDF]
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