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

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.

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