Genomic Response to Vitamin D Supplementation in the Setting of a Randomized, Placebo-Controlled Trial.
Genomic Response to Vitamin D Supplementation in the Setting of a Randomized, Placebo-Controlled Trial.
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DOI：
10.1016/j.ebiom.2018.04.010
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发表时间：
2018-05
期刊：
影响因子：
11.1
通讯作者：
Knight JC
中科院分区：
文献类型：
--
作者：
Berlanga-Taylor AJ;Plant K;Dahl A;Lau E;Hill M;Sims D;Heger A;Emberson J;Armitage J;Clarke R;Knight JC
维生素D缺乏症与多种疾病有关，但是因果关系的相关性和潜在的过程尚未完全理解。评估分子反应。
在维生素D（Best-D）的生化疗效和安全试验中，双盲，安慰剂对照，剂量找到，随机临床试验，305个社区居民65岁以上的社区居民被随机分配给维生素D3治疗4000IU，2000IU或安慰剂每天12个月。测量基线和12个月后的TNF-α）。
为12个月的维生素D分配与25-羟基维化蛋白D的血浆水平高2倍（25 [OH] D，4000IU方案），但对全血基因表达没有显着影响（FDR <5在预先指定的分析中，与安慰剂相比，％）或血浆水平。剂量维生素D方案。发现补充响应eqtls。
我们在一项随机的，安慰剂对照试验中对补充维生素D的分子进行了全面的功能分析，尽管这项研究大多仅限于65岁以上的高加索人，但结果与许多先前的研究不同，并且不支持强烈的效果。维生素D对血液或血浆细胞因子水平的长期转录组变化。在随机试验中的方法来评估分子和个体水平响应。
在一项随机的安慰剂对照试验中，在老年人中补充高剂量维生素D，对基因表达或对选定细胞因子的血浆浓度没有显着影响。
SRCTN注册中心（编号为07034656）和欧洲临床试验数据库（Eudract编号2011-005763-24）。
我们在每日维生素D补充的随机，安慰剂对照的临床试验中进行了分子分析。
参与者为高加索人，年龄> 65岁，在基线时进行了测量，安慰剂为12个月，2000 IU或4000 IU。
我们没有发现血液目的地的基因组，转录组或细胞因子在25（OH）d水平上发生巨大变化的显着差异。
许多研究报告了维生素D缺乏症与不同的疾病的关联，但对这种关联的因果关系知之甚少。众所周知，维生素D具有全基因组的作用，但结果主要来自实验室模型或人类的小型研究研究不同，可能反映了维生素D的合成和代谢的复杂性。在本研究中，我们使用了一项随机的安慰剂对照试验，但并未观察到基因（全基因组）或血浆浓度的表达显着差异社区居住的人中的精选细胞因子对于人类生理学至关重要，毫无疑问，这种影响可能会在细胞之间变化。组织，个体，种群和环境环境。未来研究维生素D的作用机理。
Vitamin D deficiency has been associated with multiple diseases, but the causal relevance and underlying processes are not fully understood. Elucidating the mechanisms of action of drug treatments in humans is challenging, but application of functional genomic approaches in randomized trials may afford an opportunity to systematically assess molecular responses. In the Biochemical Efficacy and Safety Trial of Vitamin D (BEST-D), a double-blind, placebo-controlled, dose-finding, randomized clinical trial, 305 community-dwelling individuals aged over 65 years were randomly allocated to treatment with vitamin D3 4000 IU, 2000 IU or placebo daily for 12 months. Genome-wide genotypes at baseline, and transcriptome and plasma levels of cytokines (IFN-γ, IL-10, IL-8, IL-6 and TNF-α) at baseline and after 12 months, were measured. The trial had >90% power to detect 1.2-fold changes in gene expression. Allocation to vitamin D for 12-months was associated with 2-fold higher plasma levels of 25-hydroxy-vitamin D (25[OH]D, 4000 IU regimen), but had no significant effect on whole-blood gene expression (FDR < 5%) or on plasma levels of cytokines compared with placebo. In pre-specified analysis, rs7041 (intron variant, GC) had a significant effect on circulating levels of 25(OH)D in the low dose, but not in the placebo or high dose vitamin D regimen. A gene expression quantitative trait locus analysis (eQTL) demonstrated evidence of 31,568 cis-eQTLs (unique SNP-probe pairs) among individuals at baseline and 34,254 after supplementation for 12 months (any dose). No significant associations involving vitamin D supplementation response eQTLs were found. We performed a comprehensive functional genomics and molecular analysis of vitamin D supplementation in a randomized, placebo-controlled trial. Although this study was limited to mostly Caucasian individuals aged over 65 years, the results differ from many previous studies and do not support a strong effect of vitamin D on long-term transcriptomic changes in blood or on plasma cytokine levels. The trial demonstrates the feasibility of applying functional genomic and genetic approaches in randomized trials to assess molecular and individual level responses. Supplementation with high-dose vitamin D in older people for 12 months in a randomized, placebo-controlled trial had no significant effect on gene expression or on plasma concentrations of selected cytokines. SRCTN registry (Number 07034656) and the European Clinical Trials Database (EudraCT Number 2011-005763-24). We carried out molecular analyses in a randomized, placebo-controlled, clinical trial of daily vitamin D supplementation. Participants were Caucasian, aged >65 years with measurements at baseline and 12 months for placebo, 2000 IU or 4000 IU. We did not find significant differences in genomic, transcriptomic or cytokines in blood despite large changes in 25(OH)D levels. Many studies have reported associations of vitamin D deficiency with different diseases, but little is known about the causal relevance of such associations. Genomics technologies can provide important tools for discovery and validation of disease and drug mechanisms in clinical trials, but have not been widely used. Vitamin D is known to have genome-wide effects, but results have mainly come from laboratory models or small studies in humans. Results of previous studies differ, possibly reflecting the complexity of synthesis and metabolism of vitamin D. In the present study, we used a randomized placebo-controlled trial, but did not observe any significant differences in expression in genes (genome-wide) or on plasma concentrations of selected cytokines in community-dwelling older individuals. Vitamin D is essential for human physiology and undoubtedly has multiple effects. Such effects are likely to vary between cells, tissues, individuals, populations and environmental circumstances. The mechanisms which regulate vitamin D are complex and likely to be robust to such differences. The present study shows that integrating high throughput molecular measurements is feasible in a community-based clinical trial and the results will inform future research investigating the mechanisms of action of vitamin D.
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通讯作者：
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