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

儿童对维生素 D 的经典和非经典反应：DBP g 的作用

• 批准号: 7942990
• 负责人: THOMAS O CARPENTER
• 金额: $ 49.95万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7942990
• 关键词: 25-hydroxyvitamin D; 6 year old; Achievement; Address; Affect; African American; Aldosterone; Alkaline Phosphatase; Area; Binding Proteins; Biochemical; Biological Markers; Blood Pressure; Bone Density; Child; Childhood; Data; Dihydroxycholecalciferols; Dose; Endocrine; Endocrine system; Enrollment; Environment; Ethnic Origin; Ethnic group; Fasting; Genotype; Glucose; Glycosylated Hemoglobin; Hispanics; Hydrocortisone; Immune response; Immune system; Incidence; Infant; Infection; Insulin; International Unit; Intoxication; Measures; Mediating; Minerals; Minority; Modeling; Osteocalcin; Outcome Measure; Peripheral Blood Mononuclear Cell; Phenotype; Physiological; Plasma; Population; Practice Guidelines; Predisposition; Process; Randomized; Recommendation; Recruitment Activity; Renin; Reporting; Rickets; Risk; Role; Sampling; Serum; Skeleton; Supplementation; System; Tissues; Toddler; Ultrasonography; Vitamin D; Vitamin D Deficiency; Vitamin D-Binding Protein; Vitamins; bone; cathelicidin antimicrobial peptide; cohort; development policy; inner city; insulin sensitivity; kidney cell; novel; primary outcome; public health relevance; randomized trial; response; sound

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.

描述（由申请人提供）：我们描述了我们内城地区（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）发生在超过750 6个月的13%。3岁的健康儿童在这种情况下采样。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1，25二羟维生素D [1，25（OH）2D]水平的重要预测因子。当检查这组中最常见的两个少数民族，西班牙裔和非洲裔美国人，种族和DBP基因型之间的显着相互作用是显而易见的。因此，我们怀疑维生素D的需求可能会因DBP基因型和少数民族而异。此外，DBP基因型对于解释维生素D水平和对维生素D补充的生理反应可能很重要。同样，DBP对维生素D中毒易感性的影响可能是明显的。因此，我们的研究将主要在少数民族儿童队列中检查维生素D补充剂的生理和生化反应，最容易明显的维生素D缺乏症，并按DBP基因型分层。为了检查反应，我们将重点关注维生素D的经典和新颖的非经典效应。假设1.不同DBP基因型的儿童对维生素D补充剂的反应可能不同。如果是这样，最佳维生素D补充的建议可能需要考虑DBP基因型。我们将通过确定不同水平的维生素D补充剂（每天400和1000单位）的生化反应来探索这种可能性。我们将从超过750例受试者的广泛表型队列中招募与25-OHD和1，25（OH）2D循环水平最极端差异相关的3种基因型的儿童（并根据需要招募额外的受试者），以进行这2种剂量水平的维生素D补充剂的随机试验，按3种DBP基因型组分层。这一特定目标将有助于通过评估在两种剂量水平下选定基因型中25-OHD目标水平的实现情况，为与维生素D缺乏症报告最密切相关的人口统计学中的婴儿和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，但目前尚不清楚维生素D作用的功能后果是否由DBP基因型决定。因此，我们将检查在特定目标2中进行的维生素D补充对以下方面的影响：a）维生素D对骨和矿物质系统的经典内分泌作用，结果测量包括：PTH、碱性磷酸酶活性、骨钙素、P1 NP和FGF 23的循环水平，作为维生素D对骨骼和骨矿物质密度影响的标志物（通过超声）;和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（使用来自空腹胰岛素和皮质醇水平的测量）和醛固酮和肾素的循环水平的变化。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基因型可能影响补充反应的可能性。这些数据将直接影响招募受试者的人群，即年龄在6个月至6岁之间、生活在城市环境中、患维生素D缺乏症风险最大的儿童。此外，这些数据也可能服务于更大的儿科人群。我们希望在3-4年内，这些数据可以传播，以指导政策的制定，并作为实践的指南。 公共卫生关系：这项研究将提供数据，以建立安全，有效的儿童维生素D补充生理合理的建议。我们将探讨DBP基因型可能影响补充反应的可能性。这些数据将直接影响招募受试者的人群，即年龄在6个月至6岁之间、生活在城市环境中、患维生素D缺乏症风险最大的儿童。此外，这些数据也可能服务于更大的儿科人群。