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Vitamin D Receptor Genotype, Vitamin D3 Supplementation, and Risk of Colorectal Adenomas: A Randomized Clinical Trial.

ABSTRACT: Importance:Despite epidemiological and preclinical evidence suggesting that vitamin D and calcium inhibit colorectal carcinogenesis, daily supplementation with these nutrients for 3 to 5 years was not found to significantly reduce the risk of recurrent colorectal adenomas in a recent randomized clinical trial. Objective:To investigate whether common variants in 7 vitamin D and calcium pathway genes (VDR, GC, DHCR7, CYP2R1, CYP27B1, CYP24A1, and CASR) modify the effects of vitamin D3 or calcium supplementation on colorectal adenoma recurrence. Design, Setting, and Participants:We examined 41 candidate single-nucleotide polymorphisms (SNPs) in 2259 participants in a randomized, double-blind, placebo-controlled trial conducted at 11 clinical centers in the United States. Eligibility criteria included a recently diagnosed adenoma and no remaining colorectal polyps after complete colonoscopy. The study's treatment phase ended on August 31, 2013, and the analysis for the present study took place from July 28, 2014, to October 19, 2016. Interventions:Daily oral supplementation with vitamin D3 (1000 IU) or calcium carbonate (1200 mg elemental calcium) or both or neither. Main Outcomes and Measures:The outcomes assessed were the occurrence of 1 or more adenomas or advanced adenomas (estimated diameter, ?1 cm; or with villous histologic findings, high-grade dysplasia, or cancer) during follow-up. Treatment effects and genotype associations and interactions were estimated as adjusted risk ratios (RRs) and 95% confidence intervals (CIs). The effective number of independent SNPs was calculated to correct for multiple testing. Results:Among the 2259 participants randomized, 1702 were non-Hispanic whites who completed the trial and had genotype data for analysis (1101 men; mean [SD] age 58.1 [6.8] years). The effect of vitamin D3 supplementation on advanced adenomas, but not on adenoma risk overall, significantly varied according to genotype at 2 VDR SNPs (rs7968585 and rs731236) in linkage disequilibrium (D'?=?0.98; r2?=?0.6). For rs7968585, among individuals with the AA genotype (26%), vitamin D3 supplementation reduced risk by 64% (RR, 0.36; 95% CI, 0.19-0.69; P?=?.002; absolute risk decreased from 14.4% to 5.1%). Among individuals with 1 or 2 G alleles (74%), vitamin D3 supplementation increased risk by 41% (RR, 1.41; 95% CI, 0.99-2.00; P?=?.05; absolute risk increased from 7.7% to 11.1%; P?

SUBMITTER: Barry EL

PROVIDER: S-EPMC5580351 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Vitamin D Receptor Genotype, Vitamin D3 Supplementation, and Risk of Colorectal Adenomas: A Randomized Clinical Trial.

Barry Elizabeth L EL Peacock Janet L JL Rees Judy R JR Bostick Roberd M RM Robertson Douglas J DJ Bresalier Robert S RS Baron John A JA

JAMA oncology 20170501 5

<h4>Importance</h4>Despite epidemiological and preclinical evidence suggesting that vitamin D and calcium inhibit colorectal carcinogenesis, daily supplementation with these nutrients for 3 to 5 years was not found to significantly reduce the risk of recurrent colorectal adenomas in a recent randomized clinical trial.<h4>Objective</h4>To investigate whether common variants in 7 vitamin D and calcium pathway genes (VDR, GC, DHCR7, CYP2R1, CYP27B1, CYP24A1, and CASR) modify the effects of vitamin ...[more]

PMID: 27978548

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Project description:Background & aimsThe effects of vitamin D on risk of colorectal cancer precursors are not clear. We examined the influence of vitamin D supplementation on risk of colorectal adenomas and serrated polyps in a prespecified ancillary study of a large-scale prevention trial (the vitamin D and omegA-3 trial, VITAL) of individuals who were free of cancer and cardiovascular disease at enrollment.MethodsIn VITAL trial, 25,871 adults with no history of cancer or cardiovascular disease (12,786 men 50 years or older and 13,085 women 55 years or older) were randomly assigned to groups given daily dietary supplements (2000 IU vitamin D3 and 1 g marine n-3 fatty acid) or placebo. Patients were assigned to groups from November 2011 through March 2014 and the study ended on December 31, 2017. We confirmed conventional adenomas and serrated polyps by reviewing histopathology reports from participants who had reported a diagnosis of polyps and were asked by their doctors to return for a repeat colonoscopy or sigmoidoscopy in 5 years or less. We calculated the odds ratios (ORs) and 95% CIs by logistic regression, after adjusting for age, sex, n-3 treatment assignment, and history of endoscopy at time of randomization.ResultsDuring a median follow-up of 5.3 years, we documented 308 cases of conventional adenomas in 12,927 participants in the vitamin D group and 287 cases in 12,944 participants in the placebo group (OR for the association of vitamin D supplementation with adenoma, 1.08; 95% CI, 0.92-1.27). There were 172 cases of serrated polyps in the vitamin D group and 169 cases in the placebo group (OR for the association of vitamin D supplementation with serrated polyp, 1.02; 95% CI, 0.82-1.26). Supplementation was not associated with polyp size, location, multiplicity, or histologic features. We found evidence for an interaction between vitamin D supplementation and serum level of 25-hydroxyvitamin D, measured in 15,787 participants at randomization. Among individuals with serum levels of 25-hydroxyvitamin D below 30 ng/mL, the OR associated with supplementation for conventional adenoma was 0.82 (95% CI, 0.60-1.13), whereas among individuals with serum levels of 25-hydroxyvitamin D above 30 ng/mL, the OR for conventional adenoma was 1.20 (95% CI, 0.92-1.55) (P for interaction = .07). There was a significant interaction between vitamin D supplementation and serum level of 25-hydroxyvitamin D in their association with advanced adenoma (P for interaction = .04).ConclusionsBased on an ancillary study of data from the VITAL trial, daily vitamin D supplementation (2000 IU) was not associated with risk of colorectal cancer precursors in average-risk adults not selected for vitamin D insufficiency. A potential benefit for individuals with low baseline level of vitamin D requires further investigation. ClinicalTrials.gov number: NCT01169259.

Project description:BackgroundVitamin D deficiency is associated with obesity; whether repletion supports weight loss and changes obesity-related biomarkers is unknown.ObjectiveWe compared 12 mo of vitamin D3 supplementation with placebo on weight, body composition, insulin, and C-reactive protein (CRP) in postmenopausal women in a weight-loss intervention.DesignA total of 218 overweight/obese women (50-75 y of age) with serum 25-hydroxyvitamin D [25(OH)D] ≥10 ng/mL but <32 ng/mL were randomly assigned to weight loss + 2000 IU oral vitamin D3/d or weight loss + daily placebo. The weight-loss intervention included a reduced-calorie diet (10% weight loss goal) and 225 min/wk of moderate-to-vigorous aerobic activity. Mean 12-mo changes in weight, body composition, serum insulin, CRP, and 25(OH)D were compared between groups (intent-to-treat) by using generalized estimating equations.ResultsA total of 86% of participants completed the 12-mo measurements. The mean (95% CI) change in 25(OH)D was 13.6 (11.6, 15.4) ng/mL in the vitamin D3 arm compared with -1.3 (-2.6, -0.3) ng/mL in the placebo arm (P < 0.0001). Changes in weight [-7.1 (-8.7, -5.7) compared with -7.4 (-8.1, -5.4) kg], body mass index (in kg/m(2): both -2.8), waist circumference [-4.9 (-6.7, -2.9) compared with -4.5 (-5.6, -2.6) cm], percentage body fat [-4.1 (-4.9, -2.9) compared with -3.5 (-4.5, -2.5)], trunk fat [-4.1 (-4.7, -3.0) compared with -3.7 (-4.3, -2.9) kg], insulin [-2.5 (-3.4, -1.7) compared with -2.4 (-3.3, -1.4) μU/mL], and CRP [-0.9 (-1.2, -0.6) compared with -0.79 (-0.9, -0.4) mg/L] [corrected] were similar between groups (all P > 0.05). Compared with women who achieved 25(OH)D <32 ng/mL, women randomly assigned to vitamin D who became replete (ie, 25(OH)D ≥32 ng/mL) lost more weight [-8.8 (-11.1, -6.9) compared with -5.6 (-7.2, -5.0) kg; P = 0.05], waist circumference [-6.6 (-9.3, -4.3) compared with -2.5 (-4.6, -2.0) cm; P = 0.02], and percentage body fat [-4.7 (-6.1, -3.5) compared with -2.6 (-3.9, -2.2); P = 0.04]. Among women with complete pill counts (97% adherence), the mean decrease in CRP was 1.18 mg/mL (46%) in the vitamin D arm compared with 0.46 mg/mL (25%) in the placebo arm (P = 0.03).ConclusionsVitamin D3 supplementation during weight loss did not increase weight loss or associated factors compared with placebo; however, women who became replete experienced greater improvements. This trial was registered at clinicaltrials.gov as NCT01240213.

Project description:BackgroundObese children are vulnerable to vitamin D deficiency and impaired cardiovascular health; vitamin D replenishment might improve their cardiovascular health.ObjectivesThe aims were to determine, in vitamin D-deficient overweight and obese children, whether supplementation with vitamin D3 1000 or 2000 IU/d is more effective than 600 IU/d in improving arterial endothelial function, arterial stiffness, central and systemic blood pressure (BP), insulin sensitivity (1/fasting insulin concentration), fasting glucose concentration, and lipid profile and to explore whether downregulation of adipocytokines and markers of systemic inflammation underlies vitamin D effects.MethodsWe conducted a randomized, double-masked, controlled clinical trial in 225 10- to 18-y-old eligible children. Change in endothelial function at 6 mo was the primary outcome.ResultsDose-response increases in serum 25-hydroxyvitamin D concentrations were significant and tolerated without developing hypercalcemia. Changes at 3 and 6 mo in endothelial function, arterial stiffness, systemic-systolic BP, lipids, and inflammatory markers did not differ between children receiving 1000 or 2000 IU vitamin D and children receiving 600 IU. Some secondary outcomes differed between groups. Compared with the 600-IU group, central-systolic, central-diastolic, and systemic-diastolic BP was lower at 6 mo in the 1000-IU group [-2.66 (95% CI: -5.27, -0.046), -3.57 (-5.97, -1.17), and -3.28 (-5.55, -1.00) mm Hg, respectively]; insulin sensitivity increased at 3 and 6 mo and fasting glucose concentration declined at 6 mo (-2.67; 95% CI: -4.88, -0.46 mg/dL) in the 2000-IU group.ConclusionsCorrection of vitamin D deficiency in overweight and obese children by vitamin D3 supplementation with 1000 or 2000 IU/d versus 600 IU/d did not affect measures of arterial endothelial function or stiffness, systemic inflammation, or lipid profile, but resulted in reductions in BP and fasting glucose concentration and in improvements in insulin sensitivity. Optimization of children's vitamin D status may improve their cardiovascular health. This trial was registered at clinicaltrials.gov as NCT01797302.

Project description:AIM:To prospectively evaluate the effects of vitamin D3 on disease activity and quality of life in ulcerative colitis (UC) patients with hypovitaminosis D. METHODS:The study was a prospective double-blinded, randomized trial conducted at Community Regional Medical Center, Fresno, CA from 2012-2013. Patients with UC and a serum 25(OH)D level <30 ng/ml were eligible for the study. Enrolled subjects were randomized to receive either 2,000 IU or 4,000 IU of oral vitamin D3 daily for a total of 90 days. The Short IBD Questionnaire (SIBDQ) for quality of life, the Partial Mayo Score for UC disease activity and serum lab tests were compared between the two treatment groups. Matched pair t-tests were computed to assess differences between the vitamin D levels, CRP, UC disease activity and SIBDQ scores before and after vitamin D3 therapy using SPSS version 21. RESULTS:Eight UC patients received 2,000 IU/daily and ten UC patients received 4,000 IU/daily of vitamin D3 for 90 days. Vitamin D levels increased after 90 days of oral vitamin D3 in both dose groups. However, the increase in vitamin D levels after 90 days of oral vitamin D3, in the 4,000 IU group was significantly higher 16.80 ± 9.15 (p < 0.001) compared to the 2,000 IU group of vitamin D 5.00 ± 3.12 (p = 0.008). Normal vitamin D levels (>30 ng/dl) were achieved in four out of the ten UC patients (40%) in the 4,000 IU group and in one out of the eight UC patients (12%) in the 2,000 IU group. In the group receiving 4,000 IU/day of vitamin D3 the increase in quality life scores (SIBDQ) was significant 1.0 ± 1.0 (p = 0.017) but not in the 2,000 IU vitamin D3 group 0.1 ± 1.0 (p = 0.87). In the 2,000 IU of vitamin D3 group the mean decrease in the Partial Mayo UC Score was -0.5 ± 1.5 (p = 0.38) compared to -1.3 ± 2.9 (p = 0.19) in the 4,000 IU vitamin D3 group but this was not statistically significant. CRP levels decreased after 90 days of daily vitamin D3 in both the 2,000 IU group and 4,000 IU group by -3.0 ± 9.4 (p = 0.4) and -10.8 ± 35.0 (p = 0.36) respectively. CONCLUSION:Vitamin D3 at 4,000 IU/day is more effective than 2,000 IU/day in increasing vitamin D to sufficient levels in UC patients with hypovitaminosis D, however higher doses or treatment beyond ninety days may be required. Vitamin D3 may improve the quality of life in UC patients but clinically significant improvement is not yet established. The effect of vitamin D3 on UC disease activity is still unclear. Further larger studies are needed to investigate the effects of vitamin D in ulcerative colitis.

Project description:ImportanceSevere asthma exacerbations cause significant morbidity and costs. Whether vitamin D3 supplementation reduces severe childhood asthma exacerbations is unclear.ObjectiveTo determine whether vitamin D3 supplementation improves the time to a severe exacerbation in children with asthma and low vitamin D levels.Design, setting, and participantsThe Vitamin D to Prevent Severe Asthma Exacerbations (VDKA) Study was a randomized, double-blind, placebo-controlled clinical trial of vitamin D3 supplementation to improve the time to severe exacerbations in high-risk children with asthma aged 6 to 16 years taking low-dose inhaled corticosteroids and with serum 25-hydroxyvitamin D levels less than 30 ng/mL. Participants were recruited from 7 US centers. Enrollment started in February 2016, with a goal of 400 participants; the trial was terminated early (March 2019) due to futility, and follow-up ended in September 2019.InterventionsParticipants were randomized to vitamin D3, 4000 IU/d (n = 96), or placebo (n = 96) for 48 weeks and maintained with fluticasone propionate, 176 μg/d (6-11 years old), or 220 μg/d (12-16 years old).Main outcomes and measuresThe primary outcome was the time to a severe asthma exacerbation. Secondary outcomes included the time to a viral-induced severe exacerbation, the proportion of participants in whom the dose of inhaled corticosteroid was reduced halfway through the trial, and the cumulative fluticasone dose during the trial.ResultsAmong 192 randomized participants (mean age, 9.8 years; 77 girls [40%]), 180 (93.8%) completed the trial. A total of 36 participants (37.5%) in the vitamin D3 group and 33 (34.4%) in the placebo group had 1 or more severe exacerbations. Compared with placebo, vitamin D3 supplementation did not significantly improve the time to a severe exacerbation: the mean time to exacerbation was 240 days in the vitamin D3 group vs 253 days in the placebo group (mean group difference, -13.1 days [95% CI, -42.6 to 16.4]; adjusted hazard ratio, 1.13 [95% CI, 0.69 to 1.85]; P = .63). Vitamin D3 supplementation, compared with placebo, likewise did not significantly improve the time to a viral-induced severe exacerbation, the proportion of participants whose dose of inhaled corticosteroid was reduced, or the cumulative fluticasone dose during the trial. Serious adverse events were similar in both groups (vitamin D3 group, n = 11; placebo group, n = 9).Conclusions and relevanceAmong children with persistent asthma and low vitamin D levels, vitamin D3 supplementation, compared with placebo, did not significantly improve the time to a severe asthma exacerbation. The findings do not support the use of vitamin D3 supplementation to prevent severe asthma exacerbations in this group of patients.Trial registrationClinicalTrials.gov Identifier: NCT02687815.

Project description:BackgroundAlthough there have been numerous observations of vitamin D deficiency and its links to chronic diseases, no studies have reported on how vitamin D status and vitamin D3 supplementation affects broad gene expression in humans. The objective of this study was to determine the effect of vitamin D status and subsequent vitamin D supplementation on broad gene expression in healthy adults. (Trial registration: ClinicalTrials.gov NCT01696409).Methods and findingsA randomized, double-blind, single center pilot trial was conducted for comparing vitamin D supplementation with either 400 IUs (n = 3) or 2000 IUs (n = 5) vitamin D3 daily for 2 months on broad gene expression in the white blood cells collected from 8 healthy adults in the winter. Microarrays of the 16 buffy coats from eight subjects passed the quality control filters and normalized with the RMA method. Vitamin D3 supplementation that improved serum 25-hydroxyvitamin D concentrations was associated with at least a 1.5 fold alteration in the expression of 291 genes. There was a significant difference in the expression of 66 genes between subjects at baseline with vitamin D deficiency (25(OH)D<20 ng/ml) and subjects with a 25(OH)D>20 ng/ml. After vitamin D3 supplementation gene expression of these 66 genes was similar for both groups. Seventeen vitamin D-regulated genes with new candidate vitamin D response elements including TRIM27, CD83, COPB2, YRNA and CETN3 which have been shown to be important for transcriptional regulation, immune function, response to stress and DNA repair were identified.Conclusion/significanceOur data suggest that any improvement in vitamin D status will significantly affect expression of genes that have a wide variety of biologic functions of more than 160 pathways linked to cancer, autoimmune disorders and cardiovascular disease with have been associated with vitamin D deficiency. This study reveals for the first time molecular finger prints that help explain the nonskeletal health benefits of vitamin D.Trial registrationClinicalTrials.gov NCT01696409.

Dataset Information

Vitamin D Receptor Genotype, Vitamin D3 Supplementation, and Risk of Colorectal Adenomas: A Randomized Clinical Trial.

Publications

Vitamin D Receptor Genotype, Vitamin D3 Supplementation, and Risk of Colorectal Adenomas: A Randomized Clinical Trial.

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