Clinical Trial of Vitamin D3 to Reduce Cancer Risk in Postmenopausal Women

描述(由申请人提供)：25(OH)D在老年人中普遍较低，超过60%的北美女性人口低于最佳水平。低血清25(OH)D是一个严重的问题，因为最佳的血清25(OH)D浓度对于预防癌症和其他疾病是必不可少的。目前，补充维生素D是达到足够的血清25(OH)D水平的最好方法。然而，对特定剂量的维生素D补充剂的反应，血清25(OH)D的变化因人而异，这种变化的原因尚不清楚。未知因素可能是遗传的，因为基线血清25(OH)D和对维生素D摄入的反应都是高度遗传决定的。目前，这一领域的遗传学研究很少。不同个体的血清25(OH)D反应变异的特异性基因尚不清楚。通过利用来自母公司研究(R01CA129488)的大规模、同质、独特、纵向、基于人群的高剂量维生素D干预试验样本，修订的主要目标是识别导致血清25(OH)D水平变化的遗传变异。核心假设是，对维生素D代谢和信号通路具有重要作用的基因参与了绝经后妇女血清25(OH)D水平的变化。为了验证这一假设，我们选择了8个重要的候选基因。其具体目的是：1)识别导致基线血清25(OH)D水平变化的遗传变异；2)识别导致血清25(OH)D水平反应变异的遗传变异。对于特定的目标1，样本将是非西班牙裔绝经后白人妇女的整个队列(n=2300)。目标表型为基线血清25(OH)D变异。对于特定目的2，将只使用钙(1200 mg/d)和维生素D(2000IU/d)干预组(n=1150)。表型(终点)是补充维生素D后12个月血清25(OH)D的变化。这一修改建议具有很强的创新性。它将产生更多的关键信息，并将增加父研究的价值。这是首次尝试确定导致血清25(OH)D对维生素D补充反应的变异性的遗传因素。此外，它将首次解决导致基线血清25(OH)D变化的基因是否也解释了血清25(OH)D的反应可变性。从这一修订中确定的遗传因素对于理解维生素D流行状态的群体差异的机制以及补充维生素D的个体化剂量非常重要。

DESCRIPTION (provided by applicant): Serum 25(OH)D is prevalently low in older people and more than 60% North American female populations are below the optimal level. Low serum 25(OH)D is a serious problem since optimal serum 25(OH)D concentration is essential for preventing cancer and other disorders. Currently, vitamin D supplementation is the best approach in achieving adequate serum 25(OH)D levels. However, the change in serum 25(OH)D in response to a given dose of vitamin D supplementation varies widely from person to person and the factors underlying the variability are unknown. The unknown factors are likely genetic because both baseline serum 25(OH)D and the response to vitamin D intake are highly genetically determined. Currently, few genetic studies are available in this area. The specific genes underlying the response variability in serum 25(OH)D in different individual are unknown. By taking advantage of the large-size, homogeneous, unique, longitudinal, population-based, and high-dose vitamin D intervention trial sample from the parent study (R01CA129488), the primary objective of the revision is to identify genetic variants responsible for the variability in serum 25(OH)D levels. The central hypothesis is that genes functionally important for vitamin D metabolism and signaling pathways are involved in the variation of serum 25(OH)D levels in postmenopausal women. To test this hypothesis, eight prominent candidate genes have been selected. The specific aims are to: 1) identify the genetic variants responsible for the baseline serum 25(OH)D variation; 2) identify the genetic variants responsible for the response variability in serum 25(OH)D levels. For specific aim 1, the sample will be the entire cohort (n=2300) of non-Hispanic, white postmenopausal women. The targeted phenotype is baseline serum 25(OH)D variation. For specific aim 2, only subjects in the calcium (1200 mg/d) and vitamin D (2000 IU/d) intervention group (n=1150) will be used. The phenotype (endpoint) is the change of 12-month serum 25(OH)D in response to vitamin D supplementation. This revision proposal is highly innovative. It will yield additional critical information and will add value to the parent study. It is the first attempt to identify genetic factors responsible for variability in serum 25(OH)D in response to vitamin D supplementation. In addition, for the first time, it will address whether genes responsible for baseline serum 25(OH)D variation also account for the response variability in serum 25(OH)D. The genetic factors identified from this revision are important for understanding the mechanisms accounting for population variation in prevalent vitamin D status, and for individualizing dosing with vitamin D supplementation.