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

描述（由申请人提供）：我们描述了内城地区（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佝偻病，并发现维生素D缺乏症（循环25-OHD < 20 ng/ml）在750多名6岁至3岁的健康儿童中占13%。此外，我们最近对这些儿童维生素D状况的分析表明，维生素D结合蛋白（DBP）基因型是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。当研究这一群体中两个最普遍的少数民族，西班牙裔和非裔美国人时，种族和DBP基因型之间的显著相互作用是显而易见的。因此，我们怀疑维生素D需求可能因DBP基因型和少数民族而异。此外，DBP基因型可能对维生素D水平的解释和对维生素D补充的生理反应都很重要。同样，舒张压对维生素D中毒易感性的影响可能是明显的。因此，我们的研究将主要考察少数民族儿童对维生素D补充的生理和生化反应，这些儿童最容易出现明显的维生素D缺乏症，并按DBP基因型分层。为了检验反应，我们将重点关注维生素d的经典效应和新的非经典效应。不同DBP基因型的儿童对维生素D补充的反应可能不同。如果是这样，建议最佳维生素D补充可能需要考虑DBP基因型。我们将通过测定不同维生素D补充水平（每天400和1000单位）的生化反应来探索这种可能性。我们将从750多名受试者的广泛表型队列中招募与25- ohd和125 (OH)2D循环水平最极端差异相关的3种基因型儿童（并根据需要招募额外的受试者），以这两种剂量水平进行维生素D补充的随机试验，按3 DBP基因型组分层。这一具体目标将通过评估在两种剂量水平下选定基因型的25-OHD目标水平的实现情况，帮助在与维生素D缺乏症报告最密切相关的人口统计学中为婴幼儿确定适当的剂量。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代谢物水平在不同基因型之间存在差异，但尚不清楚维生素D作用的功能后果是否由DBP基因型决定。因此，我们将在特定目标2中检查维生素D补充对以下方面的影响：a)维生素D对骨骼和矿物质系统的经典内分泌影响，结果测量包括：循环PTH水平、碱性磷酸酶活性、骨钙素、P1NP和FGF23作为维生素D对骨骼和骨矿物质密度影响的超声标记；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（根据空腹胰岛素和皮质醇水平得出的指标）以及醛固酮和肾素循环水平的变化。最后，我们将研究补充维生素D对外周血单核细胞免疫反应的影响。通过评估维生素D依赖性抗菌肽cathelicidin在补充维生素D前后的表达，本研究将为建立安全、有效的儿童维生素D补充生理合理的建议提供数据。我们将探讨DBP基因型是否可能影响对补充剂的反应。这些数据将直接影响到被招募的人群，这些儿童年龄在6个月到6岁之间，生活在城市环境中，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群。我们预计，在3-4年内，这些数据可以用于指导政策的制定，并作为实践的指导方针。

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.