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Open AccessArticle

Pharmacometabolomics of Bronchodilator Response in Asthma and the Role of Age-Metabolite Interactions

1
Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA
2
PRecisiOn Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care, Boston, MA 02215, USA
3
Department of Pediatrics, Hospital Nacional de Niños, 10101 San José, Costa Rica
4
Division of Pediatric Pulmonary Medicine, UPMC Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15224, USA
5
The Broad Institute, Cambridge, MA 02142, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this manuscript.
Metabolites 2019, 9(9), 179; https://doi.org/10.3390/metabo9090179
Received: 11 July 2019 / Revised: 29 August 2019 / Accepted: 3 September 2019 / Published: 7 September 2019
(This article belongs to the Special Issue Metabolomics and Chronic Obstructive Lung Diseases)
The role of metabolism in modifying age-related differential responses to asthma medications is insufficiently understood. The objective of this study was to determine the role of the metabolome in modifying the effect of age on bronchodilator response (BDR) in individuals with asthma. We used longitudinal measures of BDR and plasma metabolomic profiling in 565 children with asthma from the Childhood Asthma Management Program (CAMP) to identify age by metabolite interactions on BDR. The mean ages at the three studied time-points across 16 years of follow-up in CAMP were 8.8, 12.8, and 16.8 years; the mean BDRs were 11%, 9% and 8%, respectively. Of 501 identified metabolites, 39 (7.8%) demonstrated a significant interaction with age on BDR (p-value < 0.05). We were able to validate two significant interactions in 320 children with asthma from the Genetics of Asthma in Costa Rica Study; 2-hydroxyglutarate, a compound involved in butanoate metabolism (interaction; CAMP: β = −0.004, p = 1.8 × 10−4; GACRS: β = −0.015, p = 0.018), and a cholesterol ester; CE C18:1 (CAMP: β = 0.005, p = 0.006; GACRS: β = 0.023, p = 0.041) Five additional metabolites had a p-value < 0.1 in GACRS, including Gammaminobutyric acid (GABA), C16:0 CE, C20:4 CE, C18.0 CE and ribothymidine. These findings suggest Cholesterol esters and GABA may modify the estimated effect of age on bronchodilator response. View Full-Text
Keywords: bronchodilator response; age by metabolite interaction; asthma; metabolomics; pharmacometabolomics; GABA; cholesterol esters; childhood asthma management program; genetic epidemiology of asthma in Costa Rica bronchodilator response; age by metabolite interaction; asthma; metabolomics; pharmacometabolomics; GABA; cholesterol esters; childhood asthma management program; genetic epidemiology of asthma in Costa Rica
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Kelly, R.S.; Sordillo, J.E.; Lutz, S.M.; Avila, L.; Soto-Quiros, M.; Celedón, J.C.; McGeachie, M.J.; Dahlin, A.; Tantisira, K.; Huang, M.; Clish, C.B.; Weiss, S.T.; Lasky-Su, J.; Wu, A.C. Pharmacometabolomics of Bronchodilator Response in Asthma and the Role of Age-Metabolite Interactions. Metabolites 2019, 9, 179.

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