title: High-resolution metabolomics to identify urine biomarkers in corticosteroid-resistant asthmatic children.
abstract: BACKGROUND
  Corticosteroid (CS) treatment has been established as the first anti-inflammatory treatment for adults and children with asthma. However, a subset of patients fails to respond to combined systemic and inhaled CS treatment.
  
  
  OBJECTIVE
  This study was aimed at further understanding CS resistance among children with severe asthma.
  
  
  METHODS
  High-resolution metabolomics was performed on urine samples from CS-respondent (n = 15) and CS-nonrespondent (n = 15) children to determine possible urine biomarkers related to CS resistance. The metabolic phenotypes of CS responders and CS nonresponders were analyzed using bioinformatics including Manhattan plot with false- discovery rate, hierarchical cluster analysis, Kyoto Encyclopedia Genes and Genomes, and Mummichog pathway analysis.
  
  
  RESULTS
  The 2-way hierarchical cluster analysis study determined 30 metabolites showing significantly different levels between CS responders and CS nonresponders. The important metabolites annotated were 3,6-dihydronicotinic acid (126.05 m/z, RT: 106, [M+H]+), 3-methoxy-4-hydroxyphenyl(ethylene)glycol (185.05 m/z, RT: 155, [M+H]+), 3,4-dihydroxy-phenylalanine (198.07 m/z, RT: 446, [M+H]+), γ-glutamylcysteine (236.06 m/z, RT: 528, [M+S(34)+H]+), Cys-Gly, (253.06 m/z, RT: 528, [M-NH3+H]+), and reduced Flavin mononucleotide (517.0794 m/z, RT: 533, [M+NaCl]+). Tyrosine metabolism, degradation of aromatic compounds, and glutathione metabolism are suggested to be significant pathways relating to CS resistance.
  
  
  CONCLUSIONS
  High-resolution metabolomics is a promising approach in asthma research. Five candidate markers were identified to be related to CS-resistant children with severe asthma. These compounds, upon validation, may contribute further in the understanding of CS resistance among children with severe asthma through the use of urine.
authors.affiliation: College of Pharmacy, Korea University, Sejong City, Korea. Electronic address: yjhwang@korea.ac.kr.
authors.forename: Youngja H
authors.initials: YH
authors.lastname: Park
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Ga.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fitzpatrick
authors.affiliation: College of Pharmacy, Korea University, Sejong City, Korea.
authors.forename: Carl Angelo
authors.initials: CA
authors.lastname: Medriano
authors.affiliation: Department of Medicine, Emory University, Atlanta, Ga.
authors.forename: Dean P
authors.initials: DP
authors.lastname: Jones
mesh_terms: D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000652:urine*; D015415:Biomarkers / Q000652:urine; D002648:Child; D002853:Chromatography, Liquid; D004351:Drug Resistance; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D055432:Metabolomics
chemical_list: D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D015415:Biomarkers
keywords: LC-MS; Metabolomics; corticosteroid resistance; pediatric asthma