Vitamin D receptor polymorphism and the risk of colorectal adenomas: evidence of interaction with dietary vitamin D and calcium.

Laboratory studies and epidemiological investigations suggest that vitamin D plays a role in the etiology of colorectal adenomas, possibly through a mechanism mediated by the vitamin D receptor (VDR). We conducted a clinic-based case-control study to examine the association between VDR polymorphisms and colorectal adenomas. We selectively identified a random subset of 393 cases of colorectal adenomas and 406 colonoscopy-negative controls from a clinic-based case-control study conducted in the metropolitan Minneapolis/St. Paul area during 1991-1994. A self-administered questionnaire was used to collect data on dietary and supplement intake of vitamin D and calcium, as well as on demographics, physical activity, medical information, lifestyle factors, reproductive history, and anthropometry. DNA was extracted from whole blood and assayed for the BsmI VDR polymorphism using an ABI 7700 TaqMan assay. Adjusted odds ratios (OR) and 95% confidence intervals (CIs) were evaluated using logistic regression. Compared with the bb genotype (33% of controls), neither the Bb (48.8% of controls) nor the BB (18.2% of controls) genotypes was strongly associated with risk of colorectal adenomas (OR = 0.86, CI = 0.63-1.19 and OR = 0.77, CI = 0.50-1.18, respectively). However, those with the lowest tertile of vitamin D intake and the BB genotype had a lower risk of colorectal adenoma (OR = 0.24, CI = 0.08-0.76) than those with the highest tertile of intake and the bb genotype. Similarly, those with the lowest tertile of calcium intake and the BB genotype had a reduced risk of colorectal adenoma (OR = 0.34, CI = 0.11-1.06). Although it has generally been shown that higher calcium and vitamin D intake are associated with a modestly reduced risk of colorectal neoplasia, our data suggest that those with the BB BsmI VDR genotype may be at reduced risk of colorectal adenoma in the presence of lower calcium and vitamin D intake.     

Circulating vitamin D metabolites, polymorphism in vitamin D receptor, and colorectal adenoma risk.

OBJECTIVE: Vitamin D is a potential agent for the prevention of colorectal cancer possibly through mechanisms mediated by the vitamin D receptor (VDR). We investigated the association of circulating vitamin D metabolites and a genetic variant of the VDR gene with advanced colorectal adenoma, a precursor lesion of colorectal cancer. METHODS: Cases with advanced adenoma of the distal large bowel and gender- and ethnicity-matched controls with a negative sigmoidoscopy were randomly selected from participants in the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial. Genotype analysis of the VDR TaqI polymorphism was completed on 763 cases and 774 controls. Serum levels of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] were measured in a subset of 394 cases and 397 controls. RESULTS: Serum levels of 25(OH)D were inversely associated with advanced adenoma risk in women but not in men. Comparing those in the highest quintile with those in the lowest quintile, the risk for advanced adenoma decreased by 73% in women [odds ratio (OR) = 0.27, 95% confidence interval (95% CI) = 0.11-0.69; P for trend = 0.0002], while the risk did not decrease in men (OR = 1.10, 95% CI = 0.60-2.05; P for trend = 0.85). In women, 25(OH)D levels were significantly higher in current users of hormone replacement therapy (HRT) than in former or never HRT users. Neither serum 1,25(OH)(2)D nor VDR TaqI genotype was associated with advanced adenoma risk. CONCLUSION: Higher serum 25(OH)D levels were associated with decreased adenoma risk. Serum 1,25(OH)(2)D and VDR TaqI genotype were not associated with adenoma risk.     

Calcium, vitamin D, and apoptosis in the rectal epithelium.

OBJECTIVE: Decreased apoptosis in the colon is potentially an early indicator of colon cancer risk and may be influenced by calcium and vitamin D. This report describes the associations of calcium intake and 25-hydroxyvitamin D levels with apoptosis in colorectal epithelium. METHODS: Consecutive patients undergoing colonoscopies were recruited for a study designed to examine risk and etiologic factors for colorectal adenomas. Diet was assessed by food frequency questionnaire, and in one subpopulation, serum 25-hydroxyvitamin D levels were measured using an enzyme immunoassay. Apoptosis was scored from normal rectal mucosal pinch biopsies. Linear and logistic regression analyses were used to examine associations between calcium, serum vitamin D, and apoptotic scores. Data were available for 498 and 280 patients for the calcium and vitamin D analyses, respectively. RESULTS: Associations of calcium intake and vitamin D with apoptosis were modified by adenoma case-status. In an adjusted logistic regression model, patients with adenomas in the highest versus lowest tertile of dietary calcium intake had 3.4 times higher odds [95% confidence interval (CI), 0.9-12.9] of elevated apoptotic scores. In adenoma-free patients, high calcium intake was not related to apoptosis (OR, 1.2; 95% CI, 0.6-2.7). In contrast, the highest level of 25-hydroxyvitamin D was associated with higher apoptosis in adenoma-free patients (OR, 2.6; 95% CI, 1.1-6.2) and slightly lower levels in patients with adenomas (OR, 0.6; 95% CI, 0.2-2.2). CONCLUSION: These results are consistent with a calcium and vitamin D-mediated apoptotic mechanism in colon carcinogenesis.     

Dairy products, polymorphisms in the vitamin D receptor gene and colorectal adenoma recurrence

Vitamin D receptor (VDR) activation inhibits proliferation and angiogenesis in the colorectal epithelium, and inhibits metastasis of colorectal tumors. Polymorphisms in the VDR gene alter receptor cellular levels and functioning, and may confer altered susceptibility to colorectal neoplasia. We aimed to investigate the influence of VDR polymorphisms and dietary factors impacting on vitamin D metabolism on colorectal adenoma (CRA) recurrence. Data on dietary intakes of calcium, vitamin D and dairy products were collected from 853 participants in the United Kingdom Colorectal Adenoma Prevention trial, a randomized trial of aspirin and folate for CRA recurrence prevention. The VDR Cdx2, FokI, BsmI, ApaI and TaqI polymorphisms were genotyped in 546 participants with available DNA, and gene-diet interaction analyses performed in 480. Dairy product intake was inversely related to CRA recurrence risk independent of calcium and vitamin D [relative risk (RR) = 0.64; 95% confidence intervals (CIs): 0.47-0.88, for subjects in the highest compared to lowest intake tertile, p(trend) = 0.005]. Milk accounted for 60% of dairy product intake, and on analysis of milk and nonmilk dairy products separately recurrence risk in individuals in the highest tertile of milk intake was half that of lowest tertile individuals (RR = 0.52; 95% CI: 0.38-0.72, p(trend) = 3.2 x 10(-5)), whereas nonmilk dairy products did not influence recurrence. VDR polymorphism genotypes and haplotypes did not directly alter recurrence risk, but the reduction in risk associated with high dairy product intake was confined to individuals with ApaI aA/AA genotype (p(interaction) = 0.02). These findings indicate dairy products, and in particular milk, have chemopreventive activity against CRA recurrence.     

Dietary calcium, vitamin D, VDR genotypes and colorectal cancer

The vitamin D receptor (VDR) may importantly modulate risk of colorectal cancer either independently or in conjunction with calcium and vitamin D intake. We evaluate the association between calcium, vitamin D, dairy products, and VDR polymorphisms in 2 case-control studies of colon and rectal cancer (n = 2,306 cases and 2,749 controls). Dietary intake was evaluated using a detailed diet history questionnaire. Two VDR polymorphisms were evaluated: an intron 8 Bsm 1 polymorphism and a 3' untranslated region poly-A length polymorphism (designated S for short and L for long). The SS genotype reduced risk of colorectal cancer for men (odds ratio [OR] = 0.71; 95% confidence interval [CI] = 0.55-0.92). High levels of calcium intake reduced risk of rectal cancer in women (OR = 0.39; 95% CI = 0.24-0.64) but were not associated with rectal cancer in men (OR = 1.02; 95% CI = 0.66-1.56). Similar reduced rectal cancer risk among women was observed at high levels of vitamin D (OR = 0.52; 95% CI = 0.32-0.85) and low-fat dairy products (OR = 0.61; 95% CI = 0.39-0.94). High levels of sunshine exposure reduced risk of rectal cancer among those diagnosed when <60 years of age (OR = 0.62, 95% CI = 0.42-0.93). Examination of calcium in conjunction with VDR genotype showed that a significant 40% reduction in risk of rectal cancer was observed for the SS or BB VDR genotypes when calcium intake was low (p interaction = 0.01 for calcium interaction). For colon cancer, high levels of dietary intake of calcium, vitamin D, and low-fat dairy products reduced risk of cancer for the SS or BB VDR genotypes, although the p for interaction was not statistically significant. These data support previous observations that high levels of calcium and vitamin D reduce risk of rectal cancer and provide support for a weak protective effect for the SS and BB VDR genotypes. The risk associated with VDR genotype seems to depend upon the level of dietary calcium and vitamin D and tumor site.     

Dietary intake of folate and riboflavin, MTHFR C677T genotype, and colorectal adenoma risk: a Dutch case-control study.

We investigated the associations between dietary intake of folate and vitamin B2, MTHFR C677T genotype, and colorectal adenomas in a Dutch case-control study. Data of cases with at least one histologically confirmed colorectal adenoma (n = 768) and controls with no history of any type of colorectal polyp (n = 709) were included. Dietary intake was assessed using a food-frequency questionnaire. Multivariable models included age and, if appropriate, dietary folate and calcium intake. The adjusted odds ratio (OR) and 95% confidence interval (CI) for the highest compared with the lowest sex-specific tertile of intake were 1.32 (95% CI, 1.01-1.73) for folate and 0.51 (95% CI, 0.36-0.73) for vitamin B2. Folate seemed to be a risk factor, especially when vitamin B2 intake was low; vitamin B2 was inversely associated with adenomas, especially with relatively high folate intake. No association was observed between MTHFR C677T genotype and colorectal adenomas. The inverse association between vitamin B2 intake and colorectal adenoma risk seemed to be more pronounced among those with the MTHFR TT genotype. We conclude that this study does not provide evidence for a decreased colorectal adenoma risk for subjects with high dietary intake of folate. It suggests, however, an inverse association between vitamin B2 and colorectal adenomas, which may be more relevant for those with the MTHFR TT genotype.     

Association between Circulating Vitamin D,the Taq1 Vitamin D Receptor Gene Polymorphism and Colorectal Cancer Risk among Jordanians

Background: The physiological role of vitamin D extends beyond bone health and calcium-phosphate homeostasis to effects on cancer risk, mainly for colorectal cancer. Vitamin D may have an anticancer effect in colorectal cancer mediated by binding of the active form 1,25(OH)2D to the vitamin D receptor (VDR). The Taq1 VDR gene polymorphism, a C-to-T base substitution (rs731236) in exon 9 may influence its expression and function. The aim of this study wass to determine the 25(OH)D vitamin D level and to investigate the association between circulating vitamin D level and Taq1VDR gene polymorphism among Jordanian colorectal cancer patients. Materials and Methods: This case control study enrolled ninety-three patients and one hundred and two healthy Jordanian volunteers from AL-Basheer Hospital/Amman (2012-2013). Ethical approval and signed consent forms were obtained from all participants before sample collection. 25(OH)D levels were determined by competitive immunoassay Elecsys (Roche Diagnostic, France). DNA was extracted (Promega, USA) and amplified by PCR followed by VDR Taq1 restriction enzyme digestion. The genotype distribution was evaluated by pairedt-test and chi-square. Comparison between vitamin D levels among CRC and control were assessed by odds ratio with 95% confidence interval. Results: The vitamin D serum level was significantly lower among colorectal cancerpatients (8.34 ng/ml) compared to the healthy control group (21.02ng/ml). Patients deficient in vitamin D (less than 10.0 ng/ml) had increased colorectal cancer risk 19.2 fold compared to control. Only 2.2% of CRC patients had optimal vitamin D compared to 23.5% among healthy control. TT, Tt and tt Taq1 genotype frequencies among CRC cases was 35.5%, 50.5% and 14% compared to 43.1%, 41.2% and 15.7% among healthy control; respectively. CRC patients had lower mean vitamin D level among TT (8.91±4.31) and Tt (9.15±5.25) genotypescompared to control ((21.3±8.31) and (19.3±7.68); respectively. Conclusions: There is significant association between low 25(OH)D serum level and colorectal cancer risk. The VDRTaq1 polymorphism was associated with increased colorectal cancer risk among patient with VDRTaq1 TT and Tt genotypes. Understanding the functional mechanism of VDRTaq1 TT and Tt may provide a strategy for colorectal cancer prevention and treatment.     

Associations between Vitamin D Receptor (VDR) Gene Polymorphisms and Colorectal Cancer Risk and Effect Modifications of Dietary Calcium and Vitamin D in a JapanesePopulation

Much interest has been drawn to possible associations between vitamin D receptor (VDR) gene polymorphismsand colorectal cancer risk in conjunction with potentially protective effects of calcium and vitamin D. In a studyof 685 cases of colorectal cancer and 778 community controls in Japan, we examined the associations of the FokI,BsmI, ApaI, and TaqI polymorphisms with colorectal cancer risk and effect modification by dietary calciumand vitamin D. Genotypes were determined by the PCR-RFLP method. The ApaI polymorphism seemed to beassociated with a decreased risk of colorectal cancer, particularly of rectal cancer. The adjusted odds ratio ofcolorectal cancer for the ApaI AA and Aa genotypes combined versus the aa genotype was 0.83 (95% confidenceinterval [CI] 0.67-1.02), and the corresponding value for rectal cancer was 0.75 (95%CI 0.56-0.99). A decreasedrisk of colorectal cancer for the ApaI AA and Aa genotypes combined was more evident in individuals with highcalcium intake (interaction p=0.055). The FokI polymorphism seemed to be associated with a decreased risk ofcolon cancer among those with high vitamin D intake (interaction p=0.09). The BsmI and TaqI polymorphismswere unrelated to colorectal cancer risk, and the null associations were not modified by calcium or vitamin Dintake. In conclusion, the ApaI polymorphism may be associated with a decreased risk of colorectal cancer inJapanese, dependent on dietary calcium intake.     

Vitamin D receptor polymorphisms and risk of colorectal adenomas (United States)

Objective: The purpose of this study was to determine whether vitamin D receptor (VDR) gene polymorphisms influence risk of colorectal adenoma. Methods: Polymorphisms in the 5 and 3 ends of the VDR gene were genotyped for 373 colorectal adenoma cases and 394 controls. Results: Overall, there was no significant association between the 5 (FokI) or the 3 (BsmI) polymorphisms and adenoma risk. However, risk of large (>1 cm) adenomas decreased with increasing copies of the FokI f allele (p = 0.04). Compared to the FF genotype, odds ratios for the Ff and ff genotypes were 0.79 (95% CI 0.44–1.41) and 0.32 (95% CI 0.11–0.91), respectively. FokI genotype was more strongly related to large adenoma risk among subjects with low dietary calcium intake (OR_Ff = 0.48; 95% CI 0.17–1.3; OR_ff = 0.21; 95% CI 0.04–1.3), low dietary vitamin D intake (OR_Ff = 0.25; 95% CI 0.09–0.69; OR_ff = 0.22; 95% CI 0.04–1.2), or dark skin color (OR_Ff = 0.66; 95% CI 0.27–1.6; OR_ff = 0.10; 95% CI 0.01–1.0). Conclusion: These results suggest that VDR FokI genotype influences development of colorectal adenomas, and that the effect may be modified by calcium and vitamin D status.     

Modification of the inverse association between dietary vitamin D intake and colorectal cancer risk by a FokI variant supports a chemoprotective action of Vitamin D intake mediated through VDR binding

Vitamin D has anticarcinogenic properties and might influence colorectal cancer (CRC) risk, but the epidemiological evidence is inconsistent. Many mechanisms of action for vitamin D have been proposed, with some of them initiating via its binding to the vitamin D receptor (VDR). Using a large Scottish case-control study, we investigated (i) main associations between CRC, vitamin D and calcium dietary intake and 4 VDR single nucleotide polymorphisms (rs10735810, rs1544410, rs11568820, rs7975232) and (ii) interaction associations between the VDR variants, vitamin D and calcium intakes. Inverse and dose-dependent associations were found between CRC risk, dietary [Odds ratio (OR) = 0.77, 95% confidence intervals (CI) 0.63, 0.92, p-trend = 0.012] and total vitamin D (OR = 0.80, 95% CI 0.65, 0.98, p-trend = 0.014) intake in multivariable-adjusted logistic regression models, whereas neither calcium intake nor any of the VDR variants were associated with CRC. Additionally, we observed statistically significant interactions (case-control, case-only designs) between vitamin D and calcium intake and rs10735810 (p-interaction 0.02, 0.006, respectively). We conducted meta-analyses of cohort, case-control and serum studies that also showed an inverse association between dietary vitamin D intake and CRC (serum studies: combined OR = 0.70, 95% CI 0.56, 0.87). The evidence of interaction we report here further supports the inverse association between vitamin D mediated through binding to the VDR.     

Colonic epithelial cell proliferation decreases with increasing levels of serum 25-hydroxy vitamin D.

Epidemiological evidence suggests a potential role for vitamin D in colon cancer prevention. Vitamin D, absorbed from the intestine or derived from solar ultraviolet light, is metabolized in the liver to 25-hydroxyvitamin D (25-OH D(3)). Previous studies examining effects of vitamin D upon carcinogenesis have focused upon the active metabolite 1,25-dihydroxyvitamin D [1,25-(OH)(2) D(3)], which interacts with nuclear vitamin D receptors in several organs. Until recently, the metabolism of 25-OH D(3) to 1,25-(OH)(2) D(3) was believed to occur only in the kidney, but more recent studies have shown that 25-OH D(3) conversion to 1,25-(OH)(2) D(3) can occur in other tissues. We examined the association between fasting levels of 25-OH D(3), 1,25-(OH)(2) D(3), and BsmI polymorphism of the vitamin D receptor (VDR) gene with indices of colonic epithelial cell proliferation and differentiation in a chemoprevention study, after giving vitamin D or calcium and taking rectal biopsies that were incubated with bromodeoxyuridine. Vitamin D receptor polymorphism was determined by genotyping of the 3' BsmI polymorphism in intron eight of the VDR gene. No significant changes in cell proliferation or in differentiation were found in subjects between study start and end. However, fasting serum levels of 25-OH D(3) showed a highly significant decrease with whole crypt labeling index and the size of the proliferative compartment (phi h). There was no correlation between serum levels of 1,25-(OH)(2) D(3) and the proliferative parameters. Calcium supplementation induced a significant effect upon the relationship between serum 25-OH D(3) and rectal epithelial cell labeling index and phi h when studied by covariance analysis without a relationship with 1,25-(OH)(2) D(3) levels. VDR genotype did not influence the effects of serum 25-OH D(3) or serum 1,25-(OH)(2) D(3) levels upon proliferation. These data suggest that there might be a local effect of 25-OH D(3) on colonic epithelial cells through conversion of 25-OH D(3) to 1,25-(OH)(2) D(3). Subsequent studies have demonstrated the presence of 1alpha-hydroxylase mRNA in normal colorectal epithelium and in colorectal cancer. Thus, vitamin D may have an important role in determining the effects of calcium on colorectal epithelial proliferation and may explain some of the discrepancies found previously in studies that examine the direct role of calcium on the colorectal epithelium.     

Calcium, vitamin D, and risk for colorectal adenoma: dependency on vitamin D receptor BsmI polymorphism and nonsteroidal anti-inflammatory drug use?

Previous epidemiological studies have been inconclusive in demonstrating an inverse association among calcium, vitamin D, and risk for colorectal adenoma. The purpose of this analysis was to evaluate the associations among calcium and vitamin D and risk for incident, sporadic colorectal adenoma according to the vitamin D receptor BsmI polymorphism and nonsteroidal anti-inflammatory drug (NSAID) use. We analyzed data from a colonoscopy-based case-control study (n = 177 cases, 228 controls) conducted in North Carolina between 1995 and 1997. Adjusted odds ratios (ORs) comparing participants in the highest to those in the lowest tertiles of total calcium and vitamin D intakes were 0.64 [95% confidence interval (CI), 0.35-1.15], P(trend) = 0.14 and 0.69 (95% CI, 0.41-1.18), and P(trend) = 0.19, respectively. Adjusted ORs for those in the upper tertile of total calcium intake relative to those in the lower were 0.25 (95% CI, 0.08-0.80) among those who had a Bb genotype, 0.57 (95% CI, 0.18-1.82) among those who had a bb genotype, and 0.36 (95% CI, 0.15-0.85) among those who did not take NSAIDs. The ORs for the highest tertile of calcium intake was 0.05 (95% CI, 0.01-0.41), P(trend) < 0.01 among those who were Bb and did not take NSAIDs, and 0.16 (95% CI, 0.02-1.36), P(trend) = 0.47 among those who were bb and did not take NSAIDs. These data support the hypotheses that higher calcium intakes may decrease risk for colorectal neoplasms, and that such a relationship is more readily detectable among those who do not take NSAIDs, and may be strongest among those who have at least one vitamin D receptor BsmI b allele.     

Survivin downregulation is not required for T antigen knockdown mediated cell growth inhibition in MCV infected merkel cell carcinoma cells

The relationship between the biomarker of vitamin D status, 25(OH)D, and the risk for colorectal neoplasia is suggestive but equivocal. Questions remain regarding whether there are differential associations between 25(OH)D and colorectal adenoma by gender, colorectal subsite or features of baseline and recurrent adenomas. We sought to investigate the relationship between 25(OH)D and both baseline and recurrent adenoma characteristics. Our study was conducted among 2,074 participants in a pooled population of two clinical intervention trials of colorectal adenoma recurrence. A cross‐sectional analysis of 25(OH)D and baseline adenoma characteristics and a prospective study of recurrent adenomas and their characteristics were conducted. There was a statistically significant inverse association between the concentrations of 25(OH)D and the presence of three or more adenomas at baseline. Compared to participants with 25(OH)D levels of <20 ng/mL, the adjusted odds ratios (ORs) (95% condifdence intervals [CIs]) were 0.99 (0.70–1.41) for those with concentrations of ≥20 and <30 ng/mL, and 0.73 (0.50–1.06) among participants with levels of ≥30 ng/mL (p‐trend = 0.05). Baseline villous histology was also significantly inversely related to 25(OH)D levels (p‐trend = 0.04). Conversely, 25(OH)D concentrations were not associated with overall colorectal adenoma recurrence, with ORs (95% CIs) of 0.91 (0.71–1.17) and 0.95 (0.73–1.24; p‐trend = 0.85). These findings support the concept that the relationship between vitamin D and colorectal neoplasia may vary by stage of adenoma development.     

Plasma 1,25-dihydroxy- and 25-hydroxyvitamin D and adenomatous polyps of the distal colorectum.

1,25-dihydroxyvitamin D [1,25(OH)2D] inhibits proliferation and promotes differentiation of human colon cancer cell lines. Epidemiological findings, although not entirely consistent, suggest an inverse relationship between vitamin D intake and colorectal cancer and adenoma, colorectal cancer precursor lesions. We evaluated the relationship of plasma 1,25(OH)2D and 25-hydroxyvitamin D [25(OH)D] with distal colorectal adenoma among 326 matched case and control pairs (nested in the prospective Nurses' Health Study), who provided blood in 1989-1990 and who underwent endoscopy in 1989-1996. Plasma vitamin D metabolite concentrations were determined blindly by RIA. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from multiple conditional logistic regression models. Mean plasma 1,25(OH)2D and 25(OH)D levels did not significantly differ (P = 0.3 and 0.7, respectively) between cases (31.6 +/- 8.4 pg/ml and 26.4 +/- 10.6 ng/ml, respectively) and controls (32.2 +/- 8.6 pg/ml and 26.8 +/-10.2 ng/ml, respectively). However, women whose plasma 1,25(OH)2D concentration was below 26.0 pg/ml (a level typically considered to be below normal) were at increased risk of distal colorectal adenoma (OR, 1.58; 95% CI, 1.03-2.40). Compared with the lowest 1,25(OH)2D quartile, women in the second (OR, 0.64; 95% CI, 0.41-1.02), third (OR, 0.80; 95% CI, 0.50-1.30), or upper (OR, 0.71; 95% CI, 0.43-1.15) quartiles were at a statistically nonsignificant lower risk of adenoma. The relationship was stronger for large/villous adenoma and among those with consistent vitamin D intake over the 10 years prior to blood draw. Compared with women in the lowest quartile, for plasma 25(OH)D, women in the second (OR, 0.64; 95% CI, 0.41-1.00) and third (OR, 0.58; 95% CI, 0.36-0.95) quartiles were at a statistically significantly lower risk of distal colorectal adenoma, but there was no difference in risk in the top quartile (OR, 1.04; 95% CI, 0.66-1.66). We conclude that women who have low levels of circulating 1,25(OH)2D may be at higher risk of distal colorectal adenomas, but additional study is warranted.     

Circulating vitamin D and colorectal adenomas in Japanese men

Accumulating evidence suggests that vitamin D has anticarcinogenic effects. However, it is unclear whether the nutrient is involved in the early stage of colorectal carcinogenesis. We examined the association between circulating vitamin D concentrations and colorectal adenomas in Japanese men. The study subjects comprised 656 cases of colorectal adenomas and 648 controls with normal colonoscopy among male self defense officials receiving a pre‐retirement health examination between 1997 and 2004. Plasma or serum levels of 25‐hydroxyvitamin D [25(OH)D] were measured using a radioimmunoassay method. Logistic regression analysis was used to obtain odds ratios (OR) and 95% confidence intervals (CI) with adjustment for potential confounding variables. Overall, there was no measurable association between circulating 25(OH)D concentrations and colorectal adenomas. When the analysis was restricted to subjects whose blood was taken during the winter season (November–April), the prevalence odds of colorectal adenomas for the highest versus lowest quartile of 25(OH)D was statistically significantly decreased (OR = 0.58; 95% CI = 0.34–0.99). The reduction was more pronounced for the rectum (OR = 0.22) and distal colon (OR = 0.47) than for proximal colon (OR = 0.70). During the summer season (May–October), higher levels of 25(OH)D were associated with an increased odds of small, but not large, adenomas. The present study adds to evidence that high levels of circulating vitamin D measured during darker season is associated with decreased prevalence of adenomas in the distal sites of the colorectum. (Cancer Sci 2010)     

Vitamin D receptor start codon polymorphism and colorectal cancer risk: effect modification by dietary calcium and fat in Singapore Chinese

Vitamin D has been implicated as a protective agent against colorectal cancer. We hypothesized that a functional start codon polymorphism in the vitamin D receptor (VDR) influences the risk of colorectal carcinoma. We conducted a case-control study nested within a large cohort of Singapore Chinese. VDR genotypes, determined by FokI restriction endonuclease digestion of PCR-amplified DNA, were performed on 217 colorectal cancer cases and 890 controls. We found that compared with individuals carrying the FF genotype, those with Ff genotype had a 51% increase in risk of colorectal cancer and those with the ff genotype, an 84% increase in risk (P for trend = 0.01). The effect of the VDR genotype on risk appeared to be modified by both dietary calcium and fat. Among those with either low calcium or low fat intake (below the median values in controls), the risk for colorectal cancer increased in a gene-dose-dependent manner such that individuals possessing the ff genotype displayed an approximately 2.5-fold increased risk that was statistically significant. There was little evidence of a VDR genotype-colorectal cancer association among subjects with higher than median values of either dietary fat or calcium.     

Serum 25‐hydroxyvitamin D,vitamin D binding protein and risk of colorectal cancer in the Prostate,Lung, Colorectal and Ovarian Cancer Screening Trial

The potential role of vitamin D in cancer prevention has generated substantial interest, and laboratory experiments indicate several anti‐cancer properties for vitamin D compounds. Prospective studies of circulating 25‐hydroxyvitamin D [25(OH)D], the accepted biomarker of vitamin D status, suggest an inverse association with colorectal cancer risk, but with some inconsistencies. Furthermore, the direct or indirect impact of the key transport protein, vitamin D binding protein (DBP), has not been examined. We conducted a prospective study of serum 25(OH)D and DBP concentrations and colorectal cancer risk in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, based on 476 colorectal cancer cases and 476 controls, matched on age, sex, race and date of serum collection. All subjects underwent sigmoidoscopic screening at baseline and once during follow‐up. Conditional logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs). Circulating 25(OH)D was inversely associated with colorectal cancer (OR = 0.60, 95% CI 0.38–0.94 for highest versus lowest quintile, p trend 0.01). Adjusting for recognized colorectal cancer risk factors and accounting for seasonal vitamin D variation did not alter the findings. Neither circulating DBP nor the 25(OH)D:DBP molar ratio, a proxy for free circulating 25(OH)D, was associated with risk (OR = 0.82, 95% CI 0.54–1.26, and OR = 0.79, 95% CI 0.52–1.21, respectively), and DBP did not modify the 25(OH)D association. The current study eliminated confounding by colorectal cancer screening behavior, and supports an association between higher vitamin D status and substantially lower colorectal cancer risk, but does not indicate a direct or modifying role for DBP.     

In colorectal carcinoma patients, serum vitamin D levels vary according to stage of the carcinoma.

BACKGROUND: Epidemiologic studies have demonstrated an inverse correlation between dietary calcium and vitamin D intake and the incidence of colorectal carcinoma. Elevated serum levels of 25-hydroxyvitamin D3 (25-OH-D3) are associated with a major reduction in the incidence of this neoplasm. The reduction in tumor size and number induced by calcium supplements in an experimental carcinogenesis model was neutralized by vitamin D3 deficiency. To the authors' knowledge, vitamin D serum levels have never been determined previously in colorectal carcinoma patients. They compared serum 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), 25-OH-D3, and parathyroid hormone (PTH) levels of colorectal carcinoma patients with those of healthy controls. METHODS: Serum 1,25(OH)2D3, 25-OH-D3, and PTH levels were determined in 84 colorectal carcinoma patients (10 with Stage I, 29 with Stage II, 25 with Stage III, and 20 with Stage IV) and 30 healthy controls, all of whom were normocalcemic and not taking calcium or vitamin D supplements. RESULTS: 25-OH-D3 serum levels were higher in cancer patients than controls, irrespective of stage. Serum 1,25(OH)2D3 decreased with advancing stage: 73 +/- 18, 48 +/- 16, 39 +/- 12, 34 +/- 13, and 75 +/- 20 pg/mL in Stages I, II, III, IV, and controls, respectively. There was a corresponding increase in serum PTH levels: 58.0 +/- 9.4, 73.7 +/- 14.4, 79.0 +/- 21.3, 100.4 +/- 30.9, and 51.2 +/- 3.9 pg/mL in Stages I, II, III, IV, and controls, respectively. Serum vitamin D metabolite levels did not correlate with gender, age, tumor localization, or histologic grade. CONCLUSIONS: An inverse correlation between serum levels of the active metabolite of vitamin D and colorectal carcinoma stage has been demonstrated for the first time, to the authors' knowledge, in colorectal carcinoma patients. Because 1,25(OH)2D3 has been shown to inhibit proliferation of colonic epithelial cells, decreased serum levels may facilitate the growth of colorectal carcinoma and influence its biologic behavior.     

Vitamin D receptor gene polymorphisms, insulin-like growth factors, and prostate cancer risk: a population-based case-control study in China

Operating through the vitamin D receptor (VDR), vitamin D inhibits prostate cancer growth and increases insulin-like growth factor binding protein (IGFBP) expression, suggesting that the vitamin D and insulin-like growth factor (IGF) regulatory systems may operate together to affect prostate cancer. Among 191 newly diagnosed prostate cancer cases and 304 randomly selected population controls in Shanghai, China, we found no significant association between the BsmI or FokI VDR gene polymorphisms and prostate cancer risk. However, we found that among men with the ff FokI genotype, those in the highest tertile of plasma IGFBP-3 had a decreased risk versus those in the lowest tertile (odds ratio, 0.14; 95% confidence interval, 0.04-0.56; P(trend) < 0.01), whereas among men with the FF and Ff genotypes, IGFBP-3 was not associated with risk. Similarly, IGFBP-1 was inversely associated with prostate cancer risk only among men with the ff FokI genotype (odds ratio, 0.25; 95% confidence interval, 0.07-0.85; P(trend) = 0.02). No such FokI genotype-specific effects were observed for IGF-I or IGF-II. Our findings in a low-risk population suggest that the IGF and vitamin D regulatory systems may interact to affect prostate cancer risk. Larger studies are needed to confirm these findings and clarify the underlying mechanisms.     

Calcium,vitamin D,and risk of adenoma recurrence (United States)

Objective: Few data exist regarding the association between calcium intake and adenoma recurrence, and no data exist for vitamin D. We investigated the role of dietary and supplemental sources of calcium and vitamin D in the etiology of adenoma recurrence. Methods: Analyses were conducted among 1304 male and female participants in the Wheat Bran Fiber (WBF) trial of adenoma recurrence. Multiple logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results: In the fully adjusted multivariate model, the OR for participants with dietary calcium intake above 1068 versus those with intake below 698 mg/day was 0.56 (95% CI = 0.39–0.80; p-trend = 0.007). Calcium supplementation at doses above 200 mg/day did not affect risk of recurrence. Although a borderline inverse association between dietary vitamin D and recurrence was observed after adjustment for age and gender, the association weakened in the fully adjusted model (OR = 0.78 for individuals in the upper compared to the lower quartile; 95% CI = 0.54–1.13). No association was shown for supplemental sources of vitamin D. Conclusions: Results of this study indicate that a higher intake of calcium decreases the risk of adenoma recurrence by approximately 45%, whereas vitamin D has no significant effect on recurrence rates.