Asthma exacerbations are the most common health-related cause of lost school and work days and contribute substantially to the more than $50 billion dollars spent on asthma annually.1 Therefore any systematic reduction in asthma exacerbations will have a large public health impact. Asthma is a heritable disease2,3 and although a number of molecular determinants have been identified4, much remains to be understood about how these variants impact the severity of disease. Metabolic profiling, the systematic analysis of all metabolites, has been used successfully to identify new biomarkers for several diseases. Metabolites have the distinct advantage of being more proximal markers of disease processes than are transcriptional, translational or post-translational changes. Metabolic profiling is also able to capture the history of relevant past exposures such as hypermethylation and response to hypoxia, both of which are highly relevant for asthma. To date, metabolomics studies have been limited in size and scope for asthma.5,6 The metabolome remains an untapped resource and has the potential to comprehensively characterize many aspects of asthma, including the severity of disease.7,8 The over arching hypothesis of this proposal is that key metabolites will elucidate our understanding of asthma severity through the use of metabolomic profiling and the integration with other forms of molecular data. We will 1) identify individual metabolites and metabolic profiles associated with asthma severity in both untargeted and candidate approaches;2) Integrate metabolomics data with genome-wide genetic (i.e. SNP) and genomic (i.e. gene expression) data 3) identify metabolomic signatures that accurately predict asthma exacerbations and differentiate asthma severity through the integration of environmental, clinical, genetic, genomic, and metabolomics data. This will represent the largest metabolomics study in asthmatic patients to date and enable the identification of important distinctions between individuals with varying asthma severity, potentially motivating specific therapeutic and primary prevention approaches for exacerbations.
Being the most common health-related cause of lost school and work days, asthma exacerbations have a large public health impact and are a direct result of environmental triggers and molecular make-up. Metabolites have the distinct advantage of being more proximal markers of disease processes than are other biological measures and are able to capture the history of past exposures, thereby offering an untapped and promising approach to inform treatment and primary prevention of asthmatic exacerbations. We therefore propose the use of 1,500 well-characterized asthmatics from two well- established cohorts to identify metabolic contributors of asthma exacerbations through comprehensive metabolic profiling and the integration with relevant clinical, environmental, and genome-wide SNP and gene expression data.