Vitamin D, genomics, and asthma morbidity in Puerto Rican children

描述(由申请人提供)：从20世纪60年代到90年代，哮喘在工业化国家的流行率有所上升，目前影响到美国约2200万人。维生素D假说认为，维生素D不足会增加哮喘的风险和严重程度，这可能在一定程度上解释了这种上升。维生素D缺乏与多个人群中哮喘加重的风险增加有关，并可能在宿主对呼吸道病毒感染的反应中发挥作用。我们假设维生素D受体(VDR)结合是细胞特异性的，并影响与哮喘相关的途径(如对病毒感染的反应)中的基因表达，这些途径含有与维生素D水平相互作用的SNPs，从而影响哮喘风险和疾病严重程度。为了验证这一假设，在目标1中，我们将对不同剂量的骨化三醇处理的支气管上皮和平滑肌细胞中的VDR结合进行全基因组调查。然后，我们将测量用TLR激动剂处理的骨化三醇刺激的支气管上皮细胞的全基因组基因表达，以模拟病毒感染(目标2)。最后，我们将整合AIMS 1和AIMS 2的结果，以提高波多黎各儿童全基因组维生素D基因交互扫描(GWIS)的能力，以检测影响哮喘恶化风险的基因多态(AIMS 3)。这项建议应该有助于阐明维生素D在哮喘和高危少数民族儿童中的作用 这一群体(波多黎各人)尤其如此。

DESCRIPTION (provided by applicant): The prevalence of asthma in industrialized nations increased from the 1960s into the 1990s, now affecting ~22 million persons in the United States. The vitamin D hypothesis, which states that vitamin D insufficiency increases the risk and severity of asthma, may partly explain this rise. Vitamin D insufficiency is associated with increased risk of asthma exacerbations in multiple populations, and likely plays a role in host response to respiratory viral infection. We hypothesize that Vitamin D Receptor (VDR) binding is cell specific and influences gene expression in pathways that are relevant to asthma (such as response to viral infections), and that these pathways harbor SNPs that interact with vitamin D levels to influence asthma risk and disease severity. To test this hypothesis, in Aim 1 we will conduct a genome-wide survey of VDR binding in bronchial epithelial and smooth muscle cells treated with varying doses of calcitriol. We will then measure genome-wide gene expression in calcitriol-stimulated bronchial epithelial cells treated with TLR-agonists to simulate viral infecton (Aim 2). Finally, we will integrate the results from Aims 1 and 2 to improve the power of a genome-wide gene- by-vitamin D interaction scan (GWIS) in Puerto Rican children to detect polymorphisms that influence risk of asthma exacerbations (Aim 3). This proposal should help elucidate the role of vitamin D on asthma in general and in children in a high-risk ethnic minority group (Puerto Ricans) in particular.