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Metabolites. 2019 Sep 7;9(9). pii: E179. doi: 10.3390/metabo9090179.

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

Author information

1
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA. hprke@channing.harvard.edu.
2
PRecisiOn Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care, Boston, MA 02215, USA. joanne_sordillo@harvardpilgrim.org.
3
PRecisiOn Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care, Boston, MA 02215, USA. sharon.m.lutz@gmail.com.
4
Department of Pediatrics, Hospital Nacional de Niños, 10101 San José, Costa Rica. lydiana98@gmail.com.
5
Department of Pediatrics, Hospital Nacional de Niños, 10101 San José, Costa Rica. msotoqui34@yahoo.com.
6
Division of Pediatric Pulmonary Medicine, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15224, USA. juan.celedon@chp.edu.
7
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA. remmg@channing.harvard.edu.
8
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA. readh@channing.harvard.edu.
9
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA. rekgt@channing.harvard.edu.
10
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA. remhu@channing.harvard.edu.
11
The Broad Institute, Cambridge, MA 02142, USA. clary@broadinstitute.org.
12
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA. restw@channing.harvard.edu.
13
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA. rejas@channing.harvard.edu.
14
PRecisiOn Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care, Boston, MA 02215, USA. Ann.Wu@childrens.harvard.edu.

Abstract

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.

KEYWORDS:

GABA; age by metabolite interaction; asthma; bronchodilator response; childhood asthma management program; cholesterol esters; genetic epidemiology of asthma in Costa Rica; metabolomics; pharmacometabolomics

PMID:
31500319
DOI:
10.3390/metabo9090179
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