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.
|Lasky-Su, Jessica A; Zeleznik, Oana A; Eliassen, A Heather (2018) Using Metabolomics to Explore the Role of Postmenopausal Adiposity in Breast Cancer Risk. J Natl Cancer Inst 110:547-548|
|Kelly, R S; Sordillo, J E; Lasky-Su, J et al. (2018) Plasma metabolite profiles in children with current asthma. Clin Exp Allergy 48:1297-1304|
|Zeleznik, O A; Poole, E M; Lindstrom, S et al. (2018) Metabolomic analysis of 92 pulmonary embolism patients from a nested case-control study identifies metabolites associated with adverse clinical outcomes. J Thromb Haemost 16:500-507|
|Laíns, Inês; Kelly, Rachel S; Miller, John B et al. (2018) Human Plasma Metabolomics Study across All Stages of Age-Related Macular Degeneration Identifies Potential Lipid Biomarkers. Ophthalmology 125:245-254|
|Kelly, Rachel S; Giorgio, Rachel T; Chawes, Bo L et al. (2017) Applications of Metabolomics in the Study and Management of Preeclampsia; A Review of the Literature. Metabolomics 13:|
|Bowler, Russell P; Wendt, Chris H; Fessler, Michael B et al. (2017) New Strategies and Challenges in Lung Proteomics and Metabolomics. An Official American Thoracic Society Workshop Report. Ann Am Thorac Soc 14:1721-1743|
|Blighe, Kevin; Chawes, Bo L; Kelly, Rachel S et al. (2017) Vitamin D prenatal programming of childhood metabolomics profiles at age 3 y. Am J Clin Nutr 106:1092-1099|
|Kelly, Rachel S; Virkud, Yamini; Giorgio, Rachel et al. (2017) Metabolomic profiling of lung function in Costa-Rican children with asthma. Biochim Biophys Acta Mol Basis Dis 1863:1590-1595|
|Lasky-Su, Jessica; Dahlin, Amber; Litonjua, Augusto A et al. (2017) Metabolome alterations in severe critical illness and vitamin D status. Crit Care 21:193|
|Kelly, Rachel S; Dahlin, Amber; McGeachie, Michael J et al. (2017) Asthma Metabolomics and the Potential for Integrative Omics in Research and the Clinic. Chest 151:262-277|
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