Classical and non-classical responses to vitamin D in children: the role of DBP g

描述(由申请人提供)：我们描述了我们市中心地区(超过80%的少数民族)循环25-羟基维生素D(25-OHD)水平低或正常的儿童软骨病，并发现在750个月以上的6个月中有13%发生维生素D缺乏(循环25-OHD和lt；20 ng/ml)。到3岁的健康儿童在这个环境中抽样。此外，我们最近对这些儿童维生素D状况的分析显示，维生素D结合蛋白(DBP)基因是25-OHD和1，25二羟基维生素D[1，25(OH)2D]水平的重要预测因子。当研究这一群体中最普遍的两个少数民族，西班牙裔和非裔美国人时，种族和DBP基因之间的显著交互作用是显而易见的。因此，我们怀疑维生素D的需求量可能会因DBP基因的不同而不同，并在少数民族群体中有所不同。此外，DBP基因可能对维生素D水平的解释和对补充维生素D的生理反应都很重要。同样，DBP对维生素D中毒易感性的影响也很明显。因此，我们的研究将考察一组主要是少数族裔儿童对补充维生素D的生理和生化反应，这些儿童最容易受到明显的维生素D缺乏的影响，并按DBP基因分型。为了检验反应，我们将关注维生素D的经典和新的非经典效应。假设1.不同DBP基因型的儿童对补充维生素D的反应可能不同。如果是这样的话，最佳维生素D补充量的建议可能需要考虑DBP基因。我们将通过确定不同水平的维生素D补充剂(每天400和1000个单位)的生化反应来探索这种可能性。我们将从我们750多名受试者的广泛表型队列中招募与循环中25-OHD和1，25(OH)2D水平差异最大的3种基因型的儿童(并根据需要招募其他受试者)，以这两种剂量水平进行维生素D补充的随机试验，按3个DBP基因型组进行分层。这一具体目标将有助于通过评估在两种剂量水平下选定的基因型中25-OHD目标水平的实现情况，为与维生素D缺乏报告最密切相关的人口中的婴儿和学步儿童确定适当的剂量。循环1，25(OH)2D也将作为次要终点进行检查。假设2：虽然我们的初步数据表明维生素D代谢物水平在不同的基因类型之间有所不同，但尚不清楚维生素D作用的功能后果是否由DBP基因决定。因此，我们将考察针对特定目标2进行的维生素D补充对：a)维生素D对骨骼和矿物系统的经典内分泌效应，结果指标包括：循环水平的甲状旁腺素、碱性磷酸酶活性、骨钙素、P1NP和FGF23作为维生素D对骨骼和骨密度影响的超声标志物；以及b)维生素D的非经典效应，包括BMI、感染发生率、血压、胰岛素敏感性(使用空腹胰岛素和皮质醇水平的测量)以及循环中的醛固酮和肾素水平。最后，我们将检测补充维生素D对外周血单核细胞免疫反应的影响。通过评估维生素D依赖的抗菌肽长春花碱在维生素D补充前后的表达，这项研究将为建立安全、有效的儿童维生素D补充的生理学建议提供数据。我们将探讨DBP基因可能影响补充剂反应的可能性。这些数据将直接影响招募受试者的人群，即城市环境中6个月至6岁的儿童，他们患维生素D缺乏症的风险最大。此外，这些数据也可能服务于更大的儿科人口。我们预计在3-4年内可以传播这些数据，以指导政策的制定，并作为实践的指导方针。 公共卫生相关性：这项研究将为建立安全、有效的儿童维生素D补充的生理健康建议提供数据。我们将探讨DBP基因可能影响补充剂反应的可能性。这些数据将直接影响招募受试者的人群，即城市环境中6个月至6岁的儿童，他们患维生素D缺乏症的风险最大。此外，这些数据也可能服务于更大的儿科人口。

DESCRIPTION (provided by applicant): We described rickets in children in our inner city area (over 80% minorities) with either low or normal circulating 25-hydroxyvitamin D (25-OHD) levels, and have found that vitamin D deficiency (circulating 25-OHD < 20 ng/ml) occurs in 13% of over 750 6 mo. to 3 yr-old healthy children sampled in this setting. Moreover, our recent analysis of vitamin D status in these children reveals that vitamin D binding protein (DBP) genotype is a significant predictor of 25-OHD and 1,25 dihydroxyvitamin D [1,25 (OH)2D] levels. When examining the two most prevalent minorities in this group, Hispanic and African-American, significant interactions between ethnicity and DBP genotype are evident. We therefore suspect that vitamin D requirements may vary according to DBP genotype, and amongst minority ethnic groups. Moreover DBP genotype may be important for both interpretation of vitamin D levels and the physiologic response to vitamin D supplementation. Likewise, a DBP effect on susceptibility to vitamin D intoxication may be apparent. Therefore our study will examine physiologic and biochemical responses to vitamin D supplementation in a cohort of primarily minority children, most susceptible to overt vitamin D deficiency, and stratified by DBP genotypes. To examine responses we will focus on both classical and novel non-classical effects of vitamin D. Hypothesis 1. Response to vitamin D supplementation may differ among children of varying DBP genotypes. If so, recommendations for optimal vitamin D supplementation may need to consider DBP genotype. We will explore this possibility by determining the biochemical response to different levels of vitamin D supplementation (400 and 1000 units daily). We will enroll children of 3 genotypes associated with the most extreme differences in circulating levels of 25-OHD and 1,25(OH)2D from our extensively phenotyped cohort of over 750 subjects (and recruit additional subjects as needed) to perform a randomized trial of vitamin D supplementation at these 2 dosing levels, stratified by the 3 DBP genotype groups. This specific aim will aid in establishing appropriate dosing for infants and toddlers in the demographic most closely associated with reports of vitamin D deficiency by assessing the achievement of target levels of 25-OHD in the selected genotypes at the two dosing levels. Circulating 1,25 (OH)2D will also be examined as a secondary endpoint. Hypothesis 2. Although our preliminary data indicate that vitamin D metabolite levels differ across genotypes, it is not clear if the functional consequences of vitamin D actions are determined by DBP genotype. Therefore, we will examine the effect of vitamin D supplementation performed in Specific Aim 2 on: a) classical endocrine effects of vitamin D on the bone and mineral system, with outcome measures to include: circulating levels of PTH, alkaline phosphatase activity, osteocalcin, P1NP, and FGF23 as markers of a vitamin D effect on the skeleton and bone mineral density by ultrasound; and b) non- classical effects of vitamin D including changes in BMI, incidence of infection, blood pressure, insulin sensitivity (using measures derived from fasting insulin and cortisol levels) and circulating levels of aldosterone and renin. Finally, we will examine effects of vitamin D supplementation on the immune response of peripheral blood mononuclear cells. By assessing expression of the vitamin D-dependent antimicrobial peptide, cathelicidin before and after vitamin D supplementation, this study will provide data for establishing physiologically sound recommendations for safe, effective vitamin D supplementation in children. We will explore the possibility that DBP genotype may affect the response to supplementation. The data will directly impact the population from which the subjects are recruited, those children between 6 months and 6 years of age, in urban environments and at greatest risk for developing vitamin D deficiency. Moreover, the data are likely to serve the larger pediatric population as well. We expect that in 3-4 years the data could be disseminated for directing development of policy, and to serve as guidelines for practice. PUBLIC HEALTH RELEVANCE: This study will provide data for establishing physiologically sound recommendations for safe, effective vitamin D supplementation in children. We will explore the possibility that DBP genotype may affect the response to supplementation. The data will directly impact the population from which the subjects are recruited, those children between 6 months and 6 years of age, in urban environments and at greatest risk for developing vitamin D deficiency. Moreover, the data are likely to serve the larger pediatric population as well.