Lina Zgaga, Susan M. Farrington, Farhat V.N. Din, Li Yin Ooi, Dominik Glodzik, Albert Tenesa, Harry Campbell, and Malcolm G. Dunlop, University of Edinburgh and Western General Hospital; Evropi Theodoratou and Harry Campbell, University of Edinburgh, Edinburgh; Albert Tenesa, University of Edinburgh, Roslin; Susan Johnston, Glasgow Royal Infirmary, Glasgow, United Kingdom; Lina Zgaga, Trinity College Dublin, Dublin, Ireland.
J Clin Oncol. 2014 Aug 10;32(23):2430-9. doi: 10.1200/JCO.2013.54.5947. Epub 2014 Jul 7.
We investigated whether the plasma level of 25-hydroxyvitamin D (25-OHD) after a diagnosis of colorectal cancer (CRC) influences survival outcome.
We prospectively studied 1,598 patients with stage I to III CRC. We sought association between plasma 25-OHD and stage-specific survival and tested for interaction between 25-OHD level and variation at the vitamin D receptor (VDR) gene locus. Blood was sampled postoperatively, and plasma was assayed for 25-OHD by liquid chromatography-tandem mass spectrometry. VDR polymorphisms (rs1544410, rs10735810, rs7975232, rs11568820) were genotyped, and haplotypes were inferred by using BEAGLE software. We tested for association between survival and 25-OHD, VDR genotype/haplotype, and after applying a VDR genotype-25-OHD interaction term. We conducted Kaplan-Meier survival analysis and used Cox proportional hazards models to estimate adjusted hazard ratios (HRs).
We found strong associations between plasma 25-OHD concentration and CRC-specific (P = .008) and all-cause mortality (P = .003). Adjusted HRs were 0.68 (95% CI, 0.50 to 0.90) and 0.70 (95% CI, 0.55 to 0.89), respectively (highest v lowest 25-OHD tertile), particularly in stage II disease (HR, 0.44; P = .004 for CRC-specific mortality). We detected gene-environment interactions between 25-OHD concentration and rs11568820 genotype for CRC-specific (P = .008) and all-cause (P = .022) mortality, number of protective alleles (P = .004 and P = .018, respectively), and GAGC haplotype at the VDR locus for all-cause mortality (P = .008).
In patients with stage I to III CRC, postoperative plasma vitamin D is associated with clinically important differences in survival outcome, higher levels being associated with better outcome. We observed interactions between 25-OHD level and VDR genotype, suggesting a causal relationship between vitamin D and survival. The influence of vitamin D supplementation on CRC outcome will require further investigation.
我们研究了结直肠癌（CRC）诊断后血浆 25-羟维生素 D（25-OHD）水平是否影响生存结局。
我们前瞻性研究了 1598 例 I 期至 III 期 CRC 患者。我们探讨了血浆 25-OHD 与特定于阶段的生存之间的关联，并检测了 25-OHD 水平与维生素 D 受体（VDR）基因座变异之间的相互作用。术后采集血液，采用液相色谱-串联质谱法检测血浆 25-OHD。VDR 多态性（rs1544410、rs10735810、rs7975232、rs11568820）通过 BEAGLE 软件进行基因分型，并推断单倍型。我们检测了生存与 25-OHD、VDR 基因型/单倍型之间的关联，并应用 VDR 基因型-25-OHD 相互作用项后进行检测。我们进行了 Kaplan-Meier 生存分析，并使用 Cox 比例风险模型估计调整后的危险比（HR）。
我们发现血浆 25-OHD 浓度与 CRC 特异性（P=0.008）和全因死亡率（P=0.003）之间存在很强的关联。调整后的 HR 分别为 0.68（95%CI，0.50 至 0.90）和 0.70（95%CI，0.55 至 0.89）（最高与最低 25-OHD 三分位数），尤其是在 II 期疾病中（CRC 特异性死亡率的 HR，0.44；P=0.004）。我们检测到 25-OHD 浓度与 rs11568820 基因型之间的基因-环境相互作用与 CRC 特异性（P=0.008）和全因（P=0.022）死亡率、保护性等位基因数量（P=0.004 和 P=0.018）以及 VDR 基因座上的 GAGC 单倍型有关全因死亡率（P=0.008）。
在 I 期至 III 期 CRC 患者中，术后血浆维生素 D 与生存结局的重要临床差异相关，较高水平与更好的结局相关。我们观察到 25-OHD 水平与 VDR 基因型之间的相互作用，表明维生素 D 与生存之间存在因果关系。维生素 D 补充对 CRC 结局的影响需要进一步研究。
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