Pharmacometabolomics of Bronchodilator Response in Asthma and the Role of Age-Metabolite Interactions
Rachel S. Kelly,
Joanne E. Sordillo,
Sharon M. Lutz,
Lydiana Avila,
Manuel Soto-Quiros,
Juan C. Celedón,
Michael J. McGeachie,
Amber Dahlin,
Kelan Tantisira,
Mengna Huang,
Clary B. Clish,
Scott T. Weiss,
Jessica Lasky-Su,
Ann Chen Wu
Affiliations
Rachel S. Kelly
Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA
Joanne E. Sordillo
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
PRecisiOn Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care, Boston, MA 02215, USA
Lydiana Avila
Department of Pediatrics, Hospital Nacional de Niños, 10101 San José, Costa Rica
Manuel Soto-Quiros
Department of Pediatrics, Hospital Nacional de Niños, 10101 San José, Costa Rica
Juan C. Celedón
Division of Pediatric Pulmonary Medicine, UPMC Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15224, USA
Michael J. McGeachie
Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA
Amber Dahlin
Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA
Kelan Tantisira
Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA
Mengna Huang
Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA
Clary B. Clish
The Broad Institute, Cambridge, MA 02142, USA
Scott T. Weiss
Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA
Jessica Lasky-Su
Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA
Ann Chen Wu
PRecisiOn Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care, Boston, MA 02215, USA
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.
