Mechanistic insights into asthma pathogenesis through the integration of asthma genes, risk exposures, and metabolomics

项目摘要 哮喘仍然是一个主要的全球公共卫生问题，导致严重的残疾， 资源利用大多数哮喘是在6岁之前被诊断出来的， 在出生后的几年里，肺部出现了令人烦恼的症状--气喘。哮喘是一种复杂的疾病， 遗传和环境暴露有助于其发展：ORMDL 3和FADS复制良好 哮喘基因，而维生素D2-5和n-3多不饱和脂肪酸（PUFAs）6最近被确定为 哮喘的重要产前危险因素。尽管识别出这些风险因素， 对这些暴露和基因如何共同作用影响哮喘的机械理解 发展仍然未知。代谢组学分析具有作为标记物的明显优势， 反映了过去和当前导致疾病的环境和遗传暴露的累积总和。 我们初步的代谢组学工作已经成功地确定了产前暴露之间的关联 （维生素D，n-3 PUFA），哮喘基因（ORMDL 3和FADS）和代谢物，从而提供了直接的 这些风险变体如何共同作用以影响疾病发展的机制联系。 这一提议的首要假设是鞘脂和类花生酸途径在 哮喘发病机制，并可能启发哮喘基因（如ORMDL 3，FADS） 产前早期暴露（维生素D和n-3 PUFA）可导致或预防哮喘。为此 根据这项建议，我们将利用两项具有类似研究设计和随访的随机临床试验 维生素D治疗哮喘减少试验（VDAART）和哥本哈根哮喘研究， 童年（COPSAC 2010）。总之，这些研究表明，产前维生素D和n-3多不饱和脂肪酸， 补充维生素C可使生命最初3年内持续性喘息/哮喘的风险降低23%（p<0.01）， 32%6（p=0.035）。在这项提案中，我们将：1）评估母体代谢组的影响， 产前暴露对儿童代谢组的影响; 2）研究鞘脂代谢产物之间的关系 途径、ORMDL 3风险变异和产前维生素D补充对哮喘风险的影响; 促炎性和抗炎性类花生酸、FADS的遗传变异和产前n-3 PUFA之间的关系 哮喘风险的补充。这项重要研究的结果将对公共卫生具有重大意义， 阐明儿童哮喘发生的机制，并可能导致预防性治疗。 儿童哮喘的治疗策略

PROJECT SUMMARY Asthma continues to represent a major global public health problem resulting in significant disability and resource utilization. Most asthma is diagnosed before the age of six years and is preceded by episodes of troublesome lung symptoms – wheezing, in the years after birth. Asthma is a complex disease with both genetic and environmental exposures contributing to its development: ORMDL3 and FADS are well-replicated asthma genes while vitamin D2-5 and n-3 polyunsaturated fats (PUFAs)6 have recently been identified as important prenatal risk factors for asthma. Despite the identification of these risk factors, a complete mechanistic understanding of how these exposures and genes operate together to impact asthma development remains unknown. Metabolomic profiling has the distinct advantage of being a marker that reflects the cumulative sum of past and current environmental and genetic exposures leading to the disease. Our preliminary metabolomics work has successfully identified associations between prenatal exposures (Vitamin D, n-3 PUFAs), asthma genes (ORMDL3 and FADS), and metabolites, thereby providing a direct mechanistic connection of how these risk variants may operate together to influence disease development. The overarching hypothesis of this proposal is that the sphingolipid and eicosanoid pathways are important in asthma pathogenesis and may enlighten the mechanisms through which asthma genes (e.g. ORMDL3, FADS) and prenatal early life exposures (vitamin D and n-3 PUFAs) operate to cause or prevent asthma. For this proposal, we will capitalize on two randomized clinical trials with analogous study design and follow-up strategies – Vitamin D Antenatal Asthma Reduction Trial (VDAART) and Copenhagen Studies on Asthma in Childhood (COPSAC2010). Together these studies showed that prenatal vitamin D and n-3 PUFAs in supplementation reduce the risk of persistent wheeze/asthma in the first 3 years of life by 23% (p<0.01) and 32%6 (p=0.035) respectively. In this proposal we will: 1) Assess the effect of the maternal metabolome and prenatal exposures on the child metabolome; 2) Study the relationship between metabolites in the sphingolipid pathway, the ORMDL3 risk variant, and prenatal vitamin D supplementation on asthma risk; 3) Study the relationship between pro- and anti-inflammatory eicosanoids, genetic variants in FADS, and prenatal n-3 PUFA supplementation on asthma risk. Findings from this important study will have great public health importance in elucidating mechanisms involved in the development of asthma in children and could lead to preventive strategies against asthma in childhood.