Impact of Common Vitamin D–Binding Protein Isoforms on Supplemental Vitamin D3 and/or Calcium Effects on Colorectal Adenoma Recurrence Risk: A Secondary Analysis of a Randomized Clinical Trial

David Corley Gibbs; Elizabeth L Barry; Veronika Fedirko; John A Baron; Roberd M Bostick

doi:10.1001/jamaoncol.2022.6924

. 2023 Jan 26;9(4):546–551. doi: 10.1001/jamaoncol.2022.6924

Impact of Common Vitamin D–Binding Protein Isoforms on Supplemental Vitamin D₃ and/or Calcium Effects on Colorectal Adenoma Recurrence Risk

A Secondary Analysis of a Randomized Clinical Trial

David Corley Gibbs ¹, Elizabeth L Barry ², Veronika Fedirko ^1,³, John A Baron ^2,⁴, Roberd M Bostick ^1,^✉

¹Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia

²Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire

³Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston

⁴Department of Medicine, University of North Carolina School of Medicine, Chapel Hill

Accepted for Publication: October 17, 2022.

Published Online: January 26, 2023. doi:10.1001/jamaoncol.2022.6924

^✉

Corresponding Author: Roberd M. Bostick, MD, MPH, Department of Epidemiology, Rollins School of Public Health, Emory University, 1518 Clifton Rd NE, Atlanta, GA 30322 (rmbosti@emory.edu).

Author Contributions: Dr Gibbs had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Gibbs, Bostick.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Gibbs, Bostick.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Gibbs, Barry, Bostick.

Obtained funding: Barry, Baron, Bostick.

Administrative, technical, or material support: Barry, Fedirko.

Supervision: Baron, Bostick.

Conflict of Interest Disclosures: Dr Baron reported receiving grants from the National Cancer Institute (NCI) during the conduct of the study and holding a patent for chemopreventive use of calcium issued with Dartmouth College (currently not licensed). Dr Bostick reported receiving grants from the NCI during the conduct of the study. No other disclosures were reported.

Funding/Support: This work was supported by grants CA236231 (to Dr Gibbs) and CA159360 (to Dr Barry) from the NCI and the Anne and Wilson P. Franklin Foundation (to Dr Bostick).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 3.

^✉

Corresponding author.

PMCID: PMC9880863 PMID: 36701139

Key Points

Question

Do functional missense variants encoding common vitamin D–binding protein (DBP) isoforms (DBP1s, DBP1f, and DBP2) modify vitamin D₃ and/or calcium supplementation effects on colorectal adenoma recurrence risk?

Findings

In this secondary analysis of a randomized clinical trial that included 1604 patients, the presence of the DBP2-encoding GC rs4588*A allele modified the effects of vitamin D₃ and/or calcium supplementation on adenoma recurrence. Vitamin D₃ plus calcium supplementation relative to placebo statistically significantly reduced adenoma risk (by 24%) among participants with DBP2 but not among participants without DBP2.

Meaning

These findings suggest that individuals who inherit the DBP2-encoding rs4588*A allele may particularly benefit from vitamin D₃ and/or calcium supplementation for colorectal adenoma prevention.

Abstract

Importance

Variants in the vitamin D–binding protein (DBP) gene (GC) encode DBP isoforms that may affect vitamin D metabolism. However, whether these isoforms modify the effects of vitamin D₃ and/or calcium supplementation on colorectal adenoma recurrence is unclear. We hypothesized that supplementation effects may be stronger among those with the DBP2 isoform (encoded by the rs4588*A allele), which is associated with vitamin D deficiency and modified the associations of circulating vitamin D with risk for colorectal neoplasms in observational studies.

Objective

To estimate supplemental vitamin D₃ and/or calcium effects on colorectal adenoma recurrence according to 3 common DBP isoforms (DBP1s, DBP1f, DBP2) encoded by 2 missense variants: rs7041 (NG_012837.3:g.57904T>G NP_001191235.1:p.Asp432Glu) and rs4588 (NG_012837.3:g.57915C>A NP_001191235.1:p.Thr436Lys).

Design, Setting, and Participants

Secondary analysis of a randomized, double-blind, placebo-controlled clinical trial of 2259 participants with a recently diagnosed adenoma and no remaining polyps after complete colonoscopy in the US from July 1, 2004, to August 31, 2013. The current analyses were performed from August 12, 2019, to July 16, 2022.

Interventions

Daily vitamin D₃ (1000 IU), calcium (1200 mg), both, or placebo.

Main Outcomes and Measures

One or more adenomas diagnosed during 3 to 5 years of follow-up. Treatment effects were estimated according to DBP isoform as risk ratios (RRs) and 95% CIs using Poisson regression analysis.

Results

Of the 2259 participants randomized (mean [SD] age, 58 [6.8] years; 1033 [64%] men), 1604 non-Hispanic White participants (chosen to avoid population stratification bias) were included in the analysis. Among those with the DBP2 isoform (rs4588*AC or AA), the RRs (95% CI) for adenoma recurrence were 0.84 (0.72-1.00) with vitamin D₃ relative to no vitamin D₃, 0.83 (95% CI, 0.70-0.99) with calcium relative to no calcium, and 0.76 (95% CI, 0.59-0.98) with both agents relative to neither agent. Conversely, among those without DBP2 (rs4588*CC), the corresponding values were 1.08 (95% CI, 0.93-1.26; P = .03 for interaction) with vitamin D₃ relative to no vitamin D₃, 0.98 (95% CI, 0.84-1.14; P = .37 for interaction) with calcium relative to no calcium, and 1.09 (0.88-1.36; P = .03 for interaction) with both agents relative to neither agent. Among DBP2 homozygotes (rs4588*AA), the RR for adenoma recurrence was 0.57 (95% CI, 0.31-1.08) with both agents relative to neither agent.

Conclusions and Relevance

The findings of this secondary analysis of a randomized clinical trial suggest that individuals with the DBP2 isoform–encoding rs4588*A allele may particularly benefit from vitamin D₃ and/or calcium supplementation for colorectal adenoma prevention.

Trial Registration

ClinicalTrials.gov Identifier: NCT00153816

This secondary analysis of a randomized clinical trial assesses whether GC gene missense variants encoding common vitamin D–binding protein isoforms modify the effects of vitamin D₃ and/or calcium supplementation on colorectal adenoma recurrence risk.

Introduction

In the largest randomized chemoprevention trial of its kind, vitamin D₃ and/or calcium supplementation did not significantly reduce colorectal adenoma recurrence overall.¹ However, vitamin D metabolism may differ by vitamin D–binding protein (DBP) isoforms DBP1f, DBP1s, and DBP2 (also known as Gc1f, Gc1s, and Gc2) encoded by 2 missense variants of the GC gene (OMIM 139200): rs4588*C>A, which distinguishes DBP2 from the DBP1 (1s and 1f) isoforms, and rs7041*G>T, which distinguishes the DBP1s and DBP1f isoforms (Figure 1A²). Although their physiological consequences are incompletely elucidated, DBP2 relative to DBP1s and DBP1f is consistently associated with lower 25-hydroxyvitamin D (25[OH]D) concentrations (Figure 1B),^3,4 which may be mediated by DBP2’s association with lower DBP concentrations since DBP can protect 25(OH)D from excretion and prolong its circulating half-life.⁵ Additionally, in recent observational studies,^4,6 higher 25(OH)D blood concentrations were inversely associated with colorectal adenoma and carcinoma risk but only among those with the DBP2 (rs4588*A) allele.

Figure 1. — A, Combined genotypes (ie, haplotypes) of 2 missense variants of the GC gene (rs7041 and rs4588) encode 3 common vitamin D–binding protein (DBP) isoforms: DBP1f, DBP1s, and DBP2. The missense variant that distinguishes the DBP1s and DBP2 isoforms from the ancestral DBP1f isoform is shown in bold type. Note that the other possible allele combination (rs7041*G+rs4588*A) encoding the isoform known as DBPx (or Gcx) is exceedingly rare (haplotype frequency = 0.0007 in our study population; numbers are provided in the footnotes to eTable 1 in Supplement 2). B and C, Violin plots of season-standardized 25-hydroxyvitamin D (25[OH]D) (ng/mL) distributions at baseline (B) and 1-year follow-up (C) among 273 participants with only DBP1s isoforms (ie, DBP1s homozygotes [DBP1s-1s]), 16 with only DBP1f isoforms (ie, DBP1f homozygotes [DBP1f-1f]), and 69 with only DBP2 isoforms (ie, DBP2 homozygotes [DBP2-2]) (eTable 1 in Supplement 2) who were randomized to receive vitamin D₃ alone or in combination with calcium (limited to non-Hispanic White participants). The dashed line at 30 ng/mL is the cutoff for vitamin D₃ sufficiency according to Endocrine Society guidelines² (to convert nanograms per milliliter to nanomoles per liter, multiply by 2.496). Asp indicates aspartic acid; Glu, glutamic acid; Lys, lysine; and Thr, threonine.

Members of our study group previously reported vitamin D₃ vs no vitamin D₃ effects on adenoma recurrence per variant allele at rs4588 and rs7041 separately (ie, in an additive genetic model).⁷ However, that study did not investigate vitamin D₃ and/or calcium supplementation effects among individuals with and without a DBP2-encoding allele (dominant model) or consider the combined genotype (haplotype) at rs4588+rs7041 that determines various isoform combinations. The purpose of this study was to estimate supplemental D₃ and/or calcium effects on colorectal adenoma recurrence according to these 3 common DBP isoforms (DBP1f, DBP1s, DBP2) encoded by the missense variants rs4588 and rs7041.

Methods

We analyzed data from a US multicenter, randomized, double-blind, placebo-controlled clinical trial of 2259 participants in the US with a recently diagnosed adenoma and no remaining polyps after complete colonoscopy from July 1, 2004, to August 31, 2013 (described previously¹). Each center’s institutional review board approved the trial protocol (Supplement 1). Analyses were conducted from August 12, 2019, to July 16, 2022. Eligible participants had a histologically verified colorectal adenoma within 4 months of enrollment and provided written informed consent. Most participants were randomized to receive daily vitamin D₃ (1000 IU), calcium (1200 mg), both, or placebo (full factorial randomization). Women could elect to receive calcium plus random assignment to vitamin D₃ or vitamin D₃ placebo (2-arm randomization). The primary and secondary end points were any histologically verified adenoma and advanced adenoma, respectively, diagnosed by colonoscopy during follow-up. GC genotyping of rs4588 (NG_012837.3:g.57915C>A NP_001191235.1:p.Thr436Lys) and rs7041 (NG_012837.3:g.57904T>G NP_001191235.1:p.Asp432Glu) was performed using a Kompetetive Allele-Specific Polymerase chain reaction (KASP) assay (Biosearch Technologies), and baseline serum 25(OH)D was measured using a radioimmunoassay, described previously.³

We limited statistical analyses to self-reported non-Hispanic White participants to avoid potential population stratification bias. We used modified Poisson regression analysis⁸ to estimate risk ratios (RRs) and 95% CIs for those randomized to receive vitamin D₃ vs no vitamin D₃, calcium vs no calcium, and both agents vs neither agent, consistent with the trial’s original analysis.¹ Covariates included age and sex; final models excluded 25(OH)D, clinical center, screening interval, number of baseline adenomas, and variables that differed by treatment group at baseline (ie, dietary calcium intake; eTable 1 in Supplement 2), since their inclusion did not affect RRs by more than 10%. We assessed effect modification by the DBP2-encoding rs4588*A allele using dominant and additive genetic inheritance models and per rs4588+rs7041 haplotype as an interaction RR (IRR) using R haplo.stats (R Foundation for Statistical Computing). We performed analyses using R, version 3.6.3 (R Foundation for Statistical Computing). A 2-sided P < .05 was considered statistically significant. The study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

Results

Selected baseline characteristics of the participants are summarized in eTable 1 in Supplement 2. Of the 2259 participants randomized (mean [SD] age, 58 [6.8] years; 1033 [64%] men), 1604 non-Hispanic White participants with genotyping and follow-up data completed the trial (Figure 2). The mean (SD) follow-up time was 4.6 (1.3) years.

Among the 735 with the DBP2-encoding rs4588*A allele (46% of 1604 participants), the RRs were 0.84 (95% CI, 0.72-1.00) for vitamin D₃ relative to no vitamin D₃, 0.83 (95% CI, 0.70-0.99) for calcium relative to no calcium, and 0.76 (95% CI, 0.59-0.98) for both agents relative to neither agent (Table). Among the 869 without the DBP2-encoding rs4588*A allele (54%), the RRs for vitamin D₃ and/or calcium ranged from 0.98 to 1.09 and were not statistically significant.

Table. Effects of Supplemental Vitamin D₃ and/or Calcium on Adenoma Recurrence Risk According to the DBP2 Isoform–Encoding rs4588*A Allele, Assuming a Dominant Inheritance Model, in 1604 Participants.

Treatment assignment	No DBP2 inherited (rs4588*CC) (n = 869)		DBP2 inherited (rs4588*AC or AA) (n = 735)		P value for interaction^a
Treatment assignment	No. of events/total No. (%)	RR (95% CI)	No. of events/total No. (%)	RR (95% CI)	P value for interaction^a
Vitamin D₃ vs no vitamin D₃^b
No vitamin D₃	187/443 (42)	1 [Reference]	161/357 (45)	1 [Reference]	.03
Vitamin D₃	192/426 (45)	1.08 (0.93-1.26)	149/378 (39)	0.84 (0.72-1.00)	.03
Calcium vs no calcium^c
No calcium	156/330 (47)	1 [Reference]	136/279 (49)	1 [Reference]	.37
Calcium	160/330 (49)	0.98 (0.84-1.14)	114/264 (43)	0.83 (0.70-0.99)	.37
Calcium plus vitamin D₃ vs neither agent^d
Neither calcium nor vitamin D₃ (placebo)	83/183 (45)	1 [Reference]	66/122 (54)	1 [Reference]	.03
Calcium plus vitamin D₃	84/168 (50)	1.09 (0.88-1.36)	54/130 (42)	0.76 (0.59-0.98)	.03

Open in a new tab

Abbreviations: DBP, vitamin D–binding protein; RR, relative risk.

^{^a}

Wald test for interaction between treatment assignment and DBP2 (dominant model; coded 0, 1).

^{^b}

The RRs were estimated in a Poisson regression model adjusted for age, sex, and calcium treatment assignment.

^{^c}

The RRs were estimated in a Poisson regression model adjusted for age, sex, and vitamin D₃ treatment assignment. Women who chose to take calcium supplements (ie, who were in the 2-arm randomization) were excluded from these analyses.

^{^d}

The RRs were estimated in a Poisson regression model adjusted for age and sex.

The RRs for adenoma recurrence stratified by the number of DBP2-encoding alleles are presented in eTable 2 in Supplement 2. The RRs were progressively inverse among participants with additional DBP2-encoding alleles, particularly with combined supplementation: the RRs for vitamin D₃ plus calcium relative to placebo were 1.09 (95% CI, 0.88-1.36), 0.81 (95% CI, 0.61-1.09), and 0.57 (95% CI, 0.31-1.08) among those with 0, 1, and 2 DBP2-encoding alleles, respectively (P = .01 for interaction for all).

In haplotype analyses, for each DBP2 haplotype inherited over the common DBP1s haplotype, the RRs were approximately 33% lower (IRR, 0.67; 95% CI, 0.48-0.93; P = .02 for interaction) for vitamin D₃ relative to no vitamin D_3, and approximately halved (IRR, 0.48; 95% CI, 0.28-0.82; P = .008 for interaction) for both agents relative to neither agent (eTable 3 in Supplement 2).

In sensitivity and secondary supplemental analyses, our DBP2-stratified findings among participants who underwent full factorial or 2-arm randomization were similar to our overall findings (eTable 4 in Supplement 2). Also, the estimated reductions in advanced adenoma risk according to DBP2 isoform were not statistically significant (eTable 5 in Supplement 2), although the power and estimate precision was limited due to few advanced adenoma cases. In addition, in an analysis to assess whether effect modification may have been due to isoform-related differences in serum 25(OH)D concentrations, the estimated treatment effects were similar according to baseline season-standardized 25(OH)D concentrations,⁹ whether categorized as less than 20, 20 to less than 30, and greater than or equal to 30 ng/mL (to convert nanograms per milliliter to nanomoles per liter, multiply by 2.496) or by tertiles (eTable 6 in Supplement 2).

Discussion

This is the first study, to our knowledge, to report vitamin D₃ and/or calcium supplementation effects on adenoma recurrence according to DBP isoform–encoding genotypes. The stronger estimated adenoma risk reduction by vitamin D₃ supplementation with an increasing number of DBP2-encoding alleles (eTable 3 in Supplement 2) is consistent with the per-rs4588*A IRR (0.82; 95% CI, 0.69-0.98) reported previously,⁷ although the earlier trial did not report the rs4588-stratified RRs. These findings may help explain the inconsistent and non–statistically significant effects of vitamin D₃ supplementation on colorectal neoplasm risk in previous trials.^1,10

There is strong biological plausibility for our findings regarding vitamin D₃ effect modification. First, those with the DBP2 isoform–encoding rs4588*A allele may attain greater circulating 25(OH)D concentration increases in response to supplementation. In a randomized clinical trial that compared 4000 IU vitamin D₃ per day with 600 IU,¹¹ the mean (SD) 1-year 25(OH)D increase was 416% (52%) among DBP2 homozygotes (rs4588*AA) compared with 136% (16%) among individuals without DBP2 (rs4588*CC),¹¹ consistent with the current group’s previous findings of stronger vitamin D₃ supplementation effects on increasing 25(OH)D concentrations per rs4588*A allele.³ Second, DBP2 is associated with approximately 2- to 4-fold lower 25(OH)D binding affinity,¹² which may increase vitamin D bioavailability, and 2- to 3-fold higher vitamin D target-gene expression induction by 25(OH)D in vitro¹³ relative to DBP1s/DBP1f. Third, in a subset of this trial’s participants, vitamin D₃ relative to placebo statistically significantly decreased colorectal tissue expression of cyclooxygenase-2, an inflammation-related biomarker of risk for colorectal cancer, but only among those with the DBP2 isoform.¹⁴

Our findings suggest a similar but weaker pattern of effect modification by DBP2 for calcium supplementation on adenoma risk. In this group’s previous biomarker study,¹⁴ calcium supplementation, relative to placebo, statistically significantly reduced cyclooxygenase-2 colorectal tissue expression but only among individuals with the DBP2 isoform. DBP2 is associated with lower circulating DBP concentrations,⁵ which may increase parathyroid hormone secretion and calcium absorption, possibly leading to stronger supplemental calcium effects.^14,15

Strengths and Limitations

Strengths of our study include its large, multicenter study population, centralized pathology review, and excellent treatment adherence. Limitations include use of single vitamin D₃ and calcium doses; relatively small sample sizes and estimated precision for subgroup analyses, especially considering the multiple treatment groups; and insufficient sample size for estimating DBP isoform–stratified RRs among non-White participants, to whom our results may not be generalizable.

Conclusions

The findings of this secondary analysis of a randomized clinical trial suggest that individuals with the DBP2 isoform–encoding rs4588*A allele, linked to vitamin D deficiency, may particularly benefit from vitamin D₃ and/or calcium supplementation for colorectal adenoma prevention. If these findings are confirmed, genotyping for the DBP2-encoding rs4588*A allele could be clinically relevant and help guide individualized adenoma prevention recommendations.

Supplement 1.

Trial Protocol

Click here for additional data file.^{(425.9KB, pdf)}

Supplement 2.

eTable 1. Selected Baseline Characteristics of Participants According to Treatment Assignment in a Multicenter Randomized Chemoprevention Trial (n = 1604)

eTable 2. Effects of Supplemental Vitamin D3 and/or Calcium on Adenoma Recurrence Risk According to the DBP2 Isoform-Encoding rs4588*A Allele, Assuming an Additive Inheritance Model, in a Multicenter Randomized Chemoprevention Trial (n = 1604)

eTable 3. Effects of Vitamin D3 and/or Calcium Supplementation on Adenoma Risk According to DBP Isoform–Encoding Haplotypes in a Multicenter Randomized Chemoprevention Trial (n = 1604)

eTable 4. Effects of Supplemental Vitamin D3 and/or Calcium on Adenoma Recurrence Risk Among Full-Factorial and 2-Arm Randomization Groups According to the DBP2 isoform-encoding rs4588*A allele, Assuming a Dominant Inheritance Model, in a Multicenter Randomized Chemoprevention Trial (n = 1604)

eTable 5. Effects of Supplemental Vitamin D3 and/or Calcium on Advanced Adenoma Risk According to the DBP2 isoform-encoding rs4588*A Allele, Assuming a Dominant Inheritance Model, in a Multicenter Randomized Clinical Trial (n = 1592)

eTable 6. Effects of Vitamin D3 and/or Calcium Supplementation on Adenoma Risk According to Baseline Season-Standardized Circulating 25(OH)D Concentration in a Multicenter Randomized Chemoprevention Trial (n = 1604)

Click here for additional data file.^{(221.1KB, pdf)}

Supplement 3.

Data Sharing Statement

Click here for additional data file.^{(14.7KB, pdf)}

References

1.Baron JA, Barry EL, Mott LA, et al. A trial of calcium and vitamin D for the prevention of colorectal adenomas. N Engl J Med. 2015;373(16):1519-1530. doi: 10.1056/NEJMoa1500409 [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911-1930. doi: 10.1210/jc.2011-0385 [DOI] [PubMed] [Google Scholar]
3.Barry EL, Rees JR, Peacock JL, et al. Genetic variants in CYP2R1, CYP24A1, and VDR modify the efficacy of vitamin D₃ supplementation for increasing serum 25-hydroxyvitamin D levels in a randomized controlled trial. J Clin Endocrinol Metab. 2014;99(10):E2133-E2137. doi: 10.1210/jc.2014-1389 [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Gibbs DC, Fedirko V, Um C, Gross MD, Thyagarajan B, Bostick RM. Associations of circulating 25-hydroxyvitamin D₃ concentrations with incident, sporadic colorectal adenoma risk according to common vitamin D binding protein isoforms. Am J Epidemiol. 2018;187(9):1923-1930. doi: 10.1093/aje/kwy102 [DOI] [PMC free article] [PubMed] [Google Scholar]
5.Speeckaert M, Huang G, Delanghe JR, Taes YE. Biological and clinical aspects of the vitamin D binding protein (Gc-globulin) and its polymorphism. Clin Chim Acta. 2006;372(1-2):33-42. doi: 10.1016/j.cca.2006.03.011 [DOI] [PubMed] [Google Scholar]
6.Gibbs DC, Song M, McCullough ML, et al. Association of circulating vitamin D with colorectal cancer depends on vitamin D–binding protein isoforms: a pooled, nested, case-control study. J Natl Cancer Inst Cancer Spectr. 2019;4(1):pkz083. [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Barry EL, Peacock JL, Rees JR, et al. Vitamin D receptor genotype, vitamin D₃ supplementation, and risk of colorectal adenomas: a randomized clinical trial. JAMA Oncol. 2017;3(5):628-635. doi: 10.1001/jamaoncol.2016.5917 [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Zou G. A modified Poisson regression approach to prospective studies with binary data. Am J Epidemiol. 2004;159(7):702-706. doi: 10.1093/aje/kwh090 [DOI] [PubMed] [Google Scholar]
9.Gail MH, Wu J, Wang M, et al. Calibration and seasonal adjustment for matched case-control studies of vitamin D and cancer. Stat Med. 2016;35(13):2133-2148. doi: 10.1002/sim.6856 [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Lazzeroni M, Serrano D, Pilz S, Gandini S. Vitamin D supplementation and cancer: review of randomized controlled trials. Anticancer Agents Med Chem. 2013;13(1):118-125. doi: 10.2174/187152013804487281 [DOI] [PubMed] [Google Scholar]
11.Fu L, Yun F, Oczak M, Wong BY, Vieth R, Cole DE. Common genetic variants of the vitamin D binding protein (DBP) predict differences in response of serum 25-hydroxyvitamin D [25(OH)D] to vitamin D supplementation. Clin Biochem. 2009;42(10-11):1174-1177. doi: 10.1016/j.clinbiochem.2009.03.008 [DOI] [PubMed] [Google Scholar]
12.Arnaud J, Constans J. Affinity differences for vitamin D metabolites associated with the genetic isoforms of the human serum carrier protein (DBP). Hum Genet. 1993;92(2):183-188. doi: 10.1007/BF00219689 [DOI] [PubMed] [Google Scholar]
13.Chun RF, Lauridsen AL, Suon L, et al. Vitamin D–binding protein directs monocyte responses to 25-hydroxy- and 1,25-dihydroxyvitamin D. J Clin Endocrinol Metab. 2010;95(7):3368-3376. doi: 10.1210/jc.2010-0195 [DOI] [PMC free article] [PubMed] [Google Scholar]
14.Gibbs DC, Fedirko V, Baron JA, et al. Inflammation modulation by vitamin D and calcium in the morphologically normal colorectal mucosa of patients with colorectal adenoma in a clinical trial. Cancer Prev Res (Phila). 2021;14(1):65-76. doi: 10.1158/1940-6207.CAPR-20-0140 [DOI] [PMC free article] [PubMed] [Google Scholar]
15.Wang X, Sheng Z, Meng L, Su C, Trooskin S, Shapses SA. 25-Hydroxyvitamin D and vitamin D binding protein levels in patients with primary hyperparathyroidism before and after parathyroidectomy. Front Endocrinol (Lausanne). 2019;10:171. doi: 10.3389/fendo.2019.00171 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Trial Protocol

Click here for additional data file.^{(425.9KB, pdf)}

Supplement 2.

eTable 1. Selected Baseline Characteristics of Participants According to Treatment Assignment in a Multicenter Randomized Chemoprevention Trial (n = 1604)

eTable 3. Effects of Vitamin D3 and/or Calcium Supplementation on Adenoma Risk According to DBP Isoform–Encoding Haplotypes in a Multicenter Randomized Chemoprevention Trial (n = 1604)

Click here for additional data file.^{(221.1KB, pdf)}

Supplement 3.

Data Sharing Statement

Click here for additional data file.^{(14.7KB, pdf)}

[cbr220030r1] 1.Baron JA, Barry EL, Mott LA, et al. A trial of calcium and vitamin D for the prevention of colorectal adenomas. N Engl J Med. 2015;373(16):1519-1530. doi: 10.1056/NEJMoa1500409 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cbr220030r2] 2.Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911-1930. doi: 10.1210/jc.2011-0385 [DOI] [PubMed] [Google Scholar]

[cbr220030r3] 3.Barry EL, Rees JR, Peacock JL, et al. Genetic variants in CYP2R1, CYP24A1, and VDR modify the efficacy of vitamin D₃ supplementation for increasing serum 25-hydroxyvitamin D levels in a randomized controlled trial. J Clin Endocrinol Metab. 2014;99(10):E2133-E2137. doi: 10.1210/jc.2014-1389 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cbr220030r4] 4.Gibbs DC, Fedirko V, Um C, Gross MD, Thyagarajan B, Bostick RM. Associations of circulating 25-hydroxyvitamin D₃ concentrations with incident, sporadic colorectal adenoma risk according to common vitamin D binding protein isoforms. Am J Epidemiol. 2018;187(9):1923-1930. doi: 10.1093/aje/kwy102 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cbr220030r5] 5.Speeckaert M, Huang G, Delanghe JR, Taes YE. Biological and clinical aspects of the vitamin D binding protein (Gc-globulin) and its polymorphism. Clin Chim Acta. 2006;372(1-2):33-42. doi: 10.1016/j.cca.2006.03.011 [DOI] [PubMed] [Google Scholar]

[cbr220030r6] 6.Gibbs DC, Song M, McCullough ML, et al. Association of circulating vitamin D with colorectal cancer depends on vitamin D–binding protein isoforms: a pooled, nested, case-control study. J Natl Cancer Inst Cancer Spectr. 2019;4(1):pkz083. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cbr220030r7] 7.Barry EL, Peacock JL, Rees JR, et al. Vitamin D receptor genotype, vitamin D₃ supplementation, and risk of colorectal adenomas: a randomized clinical trial. JAMA Oncol. 2017;3(5):628-635. doi: 10.1001/jamaoncol.2016.5917 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cbr220030r8] 8.Zou G. A modified Poisson regression approach to prospective studies with binary data. Am J Epidemiol. 2004;159(7):702-706. doi: 10.1093/aje/kwh090 [DOI] [PubMed] [Google Scholar]

[cbr220030r9] 9.Gail MH, Wu J, Wang M, et al. Calibration and seasonal adjustment for matched case-control studies of vitamin D and cancer. Stat Med. 2016;35(13):2133-2148. doi: 10.1002/sim.6856 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cbr220030r10] 10.Lazzeroni M, Serrano D, Pilz S, Gandini S. Vitamin D supplementation and cancer: review of randomized controlled trials. Anticancer Agents Med Chem. 2013;13(1):118-125. doi: 10.2174/187152013804487281 [DOI] [PubMed] [Google Scholar]

[cbr220030r11] 11.Fu L, Yun F, Oczak M, Wong BY, Vieth R, Cole DE. Common genetic variants of the vitamin D binding protein (DBP) predict differences in response of serum 25-hydroxyvitamin D [25(OH)D] to vitamin D supplementation. Clin Biochem. 2009;42(10-11):1174-1177. doi: 10.1016/j.clinbiochem.2009.03.008 [DOI] [PubMed] [Google Scholar]

[cbr220030r12] 12.Arnaud J, Constans J. Affinity differences for vitamin D metabolites associated with the genetic isoforms of the human serum carrier protein (DBP). Hum Genet. 1993;92(2):183-188. doi: 10.1007/BF00219689 [DOI] [PubMed] [Google Scholar]

[cbr220030r13] 13.Chun RF, Lauridsen AL, Suon L, et al. Vitamin D–binding protein directs monocyte responses to 25-hydroxy- and 1,25-dihydroxyvitamin D. J Clin Endocrinol Metab. 2010;95(7):3368-3376. doi: 10.1210/jc.2010-0195 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cbr220030r14] 14.Gibbs DC, Fedirko V, Baron JA, et al. Inflammation modulation by vitamin D and calcium in the morphologically normal colorectal mucosa of patients with colorectal adenoma in a clinical trial. Cancer Prev Res (Phila). 2021;14(1):65-76. doi: 10.1158/1940-6207.CAPR-20-0140 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cbr220030r15] 15.Wang X, Sheng Z, Meng L, Su C, Trooskin S, Shapses SA. 25-Hydroxyvitamin D and vitamin D binding protein levels in patients with primary hyperparathyroidism before and after parathyroidectomy. Front Endocrinol (Lausanne). 2019;10:171. doi: 10.3389/fendo.2019.00171 [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Impact of Common Vitamin D–Binding Protein Isoforms on Supplemental Vitamin D₃ and/or Calcium Effects on Colorectal Adenoma Recurrence Risk

David Corley Gibbs, MD, PhD

Elizabeth L Barry, PhD

Veronika Fedirko, PhD, MPH

John A Baron, MD

Roberd M Bostick, MD, MPH

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Interventions

Main Outcomes and Measures

Results

Conclusions and Relevance

Trial Registration

Introduction

Figure 1. Vitamin D–Binding Protein Isoforms and Their Associations With Circulating Vitamin D₃.

Methods

Results

Figure 2. Study Enrollment and Randomization Flowchart.

Table. Effects of Supplemental Vitamin D₃ and/or Calcium on Adenoma Recurrence Risk According to the DBP2 Isoform–Encoding rs4588*A Allele, Assuming a Dominant Inheritance Model, in 1604 Participants.

Discussion

Strengths and Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

Impact of Common Vitamin D–Binding Protein Isoforms on Supplemental Vitamin D3 and/or Calcium Effects on Colorectal Adenoma Recurrence Risk

David Corley Gibbs, MD, PhD

Elizabeth L Barry, PhD

Veronika Fedirko, PhD, MPH

John A Baron, MD

Roberd M Bostick, MD, MPH

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Interventions

Main Outcomes and Measures

Results

Conclusions and Relevance

Trial Registration

Introduction

Figure 1. Vitamin D–Binding Protein Isoforms and Their Associations With Circulating Vitamin D3.

Methods

Results

Figure 2. Study Enrollment and Randomization Flowchart.

Table. Effects of Supplemental Vitamin D3 and/or Calcium on Adenoma Recurrence Risk According to the DBP2 Isoform–Encoding rs4588*A Allele, Assuming a Dominant Inheritance Model, in 1604 Participants.

Discussion

Strengths and Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases

Impact of Common Vitamin D–Binding Protein Isoforms on Supplemental Vitamin D₃ and/or Calcium Effects on Colorectal Adenoma Recurrence Risk

Figure 1. Vitamin D–Binding Protein Isoforms and Their Associations With Circulating Vitamin D₃.

Table. Effects of Supplemental Vitamin D₃ and/or Calcium on Adenoma Recurrence Risk According to the DBP2 Isoform–Encoding rs4588*A Allele, Assuming a Dominant Inheritance Model, in 1604 Participants.