Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia.
Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
JAMA Oncol. 2023 Apr 1;9(4):546-551. doi: 10.1001/jamaoncol.2022.6924.
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.
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.
Daily vitamin D3 (1000 IU), calcium (1200 mg), both, or placebo.
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.
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 (rs4588AC 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 (rs4588CC), 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.
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.
ClinicalTrials.gov Identifier: NCT00153816.
维生素 D 结合蛋白（DBP）基因（GC）的变异体编码 DBP 同工型，这些同工型可能影响维生素 D 代谢。然而，这些同工型是否会改变维生素 D3 和/或钙补充对结直肠腺瘤复发的影响尚不清楚。我们假设，在 DBP2 同工型（由 rs4588*A 等位基因编码）的个体中，补充效果可能更强，该同工型与维生素 D 缺乏有关，并在观察性研究中改变了循环维生素 D 与结直肠肿瘤风险的关联。
根据 2 个错义变异体 rs7041（NG_012837.3：g.57904T>G NP_001191235.1：p.Asp432Glu）和 rs4588（NG_012837.3：g.57915C>A NP_001191235.1：p.Thr436Lys）编码的 3 种常见 DBP 同工型（DBP1s、DBP1f、DBP2），估计补充维生素 D3 和/或钙对结直肠腺瘤复发的影响。
设计、地点和参与者：在美国，从 2004 年 7 月 1 日至 2013 年 8 月 31 日，对最近诊断为腺瘤且结肠镜检查后无剩余息肉的 2259 名参与者进行了一项随机、双盲、安慰剂对照的临床试验的二次分析。目前的分析于 2019 年 8 月 12 日至 2022 年 7 月 16 日进行。
每日维生素 D3（1000 IU）、钙（1200 mg）、两者或安慰剂。
在 3 至 5 年的随访期间诊断出一个或多个腺瘤。使用泊松回归分析，根据 DBP 同工型，使用风险比（RR）和 95%置信区间（CI）估计治疗效果。
在随机分组的 2259 名参与者中（平均[SD]年龄，58[6.8]岁；1033[64%]名男性），纳入了 1604 名非西班牙裔白人参与者（选择避免人群分层偏差）进行分析。在 DBP2 同工型（rs4588AC 或 AA）的个体中，与无维生素 D3 相比，维生素 D3 组的腺瘤复发 RR（95%CI）为 0.84（0.72-1.00），与无钙相比，钙组为 0.83（95%CI，0.70-0.99），与两者均无相比，两者均为 0.76（95%CI，0.59-0.98）。相反，在没有 DBP2（rs4588CC）的个体中，相应的值分别为与无维生素 D3 相比，维生素 D3 组为 1.08（95%CI，0.93-1.26；P=0.03 用于交互作用），与无钙相比，钙组为 0.98（95%CI，0.84-1.14；P=0.37 用于交互作用），与两者均无相比，两者均为 1.09（95%CI，0.88-1.36；P=0.03 用于交互作用）。在 DBP2 纯合子（rs4588*AA）中，与两者均无相比，维生素 D3 和/或钙联合治疗的腺瘤复发 RR 为 0.57（95%CI，0.31-1.08）。
这项随机临床试验的二次分析结果表明，DBP2 同工型编码的 rs4588*A 等位基因的个体可能特别受益于维生素 D3 和/或钙补充剂，以预防结直肠腺瘤。
ClinicalTrials.gov 标识符：NCT00153816。
