title: The metabolomics of asthma control: a promising link between genetics and disease.
abstract: Short-acting β agonists (e.g., albuterol) are the most commonly used medications for asthma, a disease that affects over 300 million people in the world. Metabolomic profiling of asthmatics taking β agonists presents a new and promising resource for identifying the molecular determinants of asthma control. The objective is to identify novel genetic and biochemical predictors of asthma control using an integrative "omics" approach. We generated lipidomic data by liquid chromatography tandem mass spectrometry (LC-MS), - using plasma samples from 20 individuals with asthma. The outcome of interest was a binary indicator of asthma control defined by the use of albuterol inhalers in the preceding week. We integrated metabolomic data with genome-wide genotype, gene expression, and methylation data of this cohort to identify genomic and molecular indicators of asthma control. A Conditional Gaussian Bayesian Network (CGBN) was generated using the strongest predictors from each of these analyses. Integrative and metabolic pathway over-representation analyses (ORA) identified enrichment of known biological pathways within the strongest molecular determinants. Of the 64 metabolites measured, 32 had known identities. The CGBN model based on four SNPs (rs9522789, rs7147228, rs2701423, rs759582) and two metabolites-monoHETE_0863 and sphingosine-1-phosphate (S1P) could predict asthma control with an AUC of 95%. Integrative ORA identified 17 significantly enriched pathways related to cellular immune response, interferon signaling, and cytokine-related signaling, for which arachidonic acid, PGE2 and S1P, in addition to six genes (CHN1, PRKCE, GNA12, OASL, OAS1, and IFIT3) appeared to drive the pathway results. Of these predictors, S1P, GNA12, and PRKCE were enriched in the results from integrative and metabolic ORAs. Through an integrative analysis of metabolomic, genomic, and methylation data from a small cohort of asthmatics, we implicate altered metabolic pathways, related to sphingolipid metabolism, in asthma control. These results provide insight into the pathophysiology of asthma control.
authors.affiliation: Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School Boston, Massachusetts, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McGeachie
authors.affiliation: Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School Boston, Massachusetts, USA.
authors.forename: Amber
authors.initials: A
authors.lastname: Dahlin
authors.affiliation: Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School Boston, Massachusetts, USA.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Qiu
authors.affiliation: Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School Boston, Massachusetts, USA.
authors.forename: Damien C
authors.initials: DC
authors.lastname: Croteau-Chonka
authors.affiliation: Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School Boston, Massachusetts, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Savage
authors.affiliation: Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School Boston, Massachusetts, USA ; Children's Hospital and Harvard Medical School Boston, Massachusetts, USA ; Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute Boston, Massachusetts, USA.
authors.forename: Ann Chen
authors.initials: AC
authors.lastname: Wu
authors.affiliation: Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School Boston, Massachusetts, USA.
authors.forename: Emily S
authors.initials: ES
authors.lastname: Wan
authors.affiliation: Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School Boston, Massachusetts, USA.
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Sordillo
authors.affiliation: Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School Boston, Massachusetts, USA.
authors.forename: Amal
authors.initials: A
authors.lastname: Al-Garawi
authors.affiliation: Arizona Respiratory Center and BIO5 Institute, University of Arizona Tucson, Arizona, USA.
authors.forename: Fernando D
authors.initials: FD
authors.lastname: Martinez
authors.affiliation: Department of Pediatrics, Division of Allergy, Immunology and Pulmonary Medicine, Washington University School of Medicine St. Louis, Missouri, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Strunk
authors.affiliation: University of Wisconsin School of Medicine and Public Health Madison, Wisconsin, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Lemanske
authors.affiliation: Department of Pediatrics, Division of Allergy and Clinical Immunology, National Jewish Health and University of Colorado School of Medicine Denver, Colorado, USA.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Liu
authors.affiliation: Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School Boston, Massachusetts, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Raby
authors.affiliation: Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School Boston, Massachusetts, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Weiss
authors.affiliation: Broad Institute Cambridge, Massachusetts, USA.
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.affiliation: Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School Boston, Massachusetts, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Lasky-Su
keywords: Albuterol; asthma; epigenetics; genetics; metabolomics