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

项目总结 哮喘仍然是一个重大的全球公共卫生问题，导致严重的残疾和 资源利用率。大多数哮喘是在六岁之前被诊断出来的，在此之前会出现 令人烦恼的肺部症状--在出生后的几年里，出现喘息。哮喘是一种既有哮喘又有哮喘的复杂疾病 遗传和环境暴露促进了它的发展：ORMDL3和FADS被很好地复制 哮喘基因而维生素D2-5和n-3多不饱和脂肪(PUFAs)6最近被鉴定为 哮喘的重要产前危险因素。尽管确定了这些风险因素，但一个完整的 对这些暴露和基因如何共同作用影响哮喘的机械性理解 发展情况仍不得而知。代谢组谱有一个明显的优势，就是作为一种标记 反映过去和当前导致疾病的环境和基因暴露的累积总和。 我们的初步代谢组学工作已经成功地确定了产前暴露之间的联系 (维生素D，n-3多不饱和脂肪酸)、哮喘基因(ORMDL3和FADS)和代谢物，从而提供直接的 这些风险变量如何共同作用以影响疾病发展的机制联系。 这一建议的首要假设是鞘磷脂和二十烷醇途径在 哮喘的发病机制，并可能揭示哮喘基因(如ORMDL3、FADS) 产前早期接触(维生素D和n-3多不饱和脂肪酸)可引起或预防哮喘。为了这个 建议，我们将利用两个随机临床试验，具有类似的研究设计和随访 战略-维生素D产前哮喘缓解试验(VDAART)和哥本哈根哮喘研究 《童年》(COPSAC2010)。这些研究表明，胎儿体内的维生素D和n-3多不饱和脂肪酸 补充剂可将出生后头3年持续喘息/哮喘的风险降低23%(p&lt；0.01) 32%6(P=0.035)。在这项建议中，我们将：1)评估母体代谢组和 胎儿期暴露对儿童代谢组的影响；2)鞘磷脂代谢物之间的关系 途径、ORMDL3风险变量和产前补充维生素D对哮喘风险的影响；3)研究 促炎和抗炎二十烷类化合物、FADS基因变异与产前n-3多不饱和脂肪酸的关系 对哮喘风险的补充。这项重要研究的结果将对中国的公共卫生产生重大影响 阐明参与儿童哮喘发展的机制，并可能导致预防 儿童时期防治哮喘的策略。

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.