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

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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.