High resolution metabolomics to identify urine biomarkers in corticosteroid resistant asthmatic children

• Published in: Journal of allergy and clinical immunology 2017-05, Vol.139 (5), p.1518-1524.e4
• Main Authors: Park, Youngja H., PhD, Fitzpatrick, Anne M., PhD, Medriano, Carl Angelo, MEng, Jones, Dean P., PhD
• Format: Article
• Language: English
• Subjects: Adolescent; Adrenal Cortex Hormones - therapeutic use; Allergy and Immunology; Anti-Inflammatory Agents - therapeutic use; Aromatic compounds; Asthma; Asthma - drug therapy; Asthma - urine; Bioinformatics; Biomarkers; Biomarkers - urine; Child; Children; Chromatography; Chromatography, Liquid; Consent; corticosteroid resistance; Corticosteroids; Degradation; Drug Resistance; Encyclopedias; Ethylene; Female; Flavin mononucleotide; Genomes; Glutathione; High resolution; Humans; Immunomodulators; Inflammation; LC-MS; Male; Mass Spectrometry; Metabolism; Metabolites; Metabolomics; NMR; Nuclear magnetic resonance; Oxidative stress; pediatric asthma; Phenylalanine; Review boards; Scientific imaging; Signal transduction; Sodium chloride; Tyrosine; Urine; γ-Glutamylcysteine
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2016.08.018

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 is aimed at further understanding CS resistance among severe asthmatic children. Methods High resolution metabolomics (HRM) 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 (FDR), hierarchical cluster analysis (HCA), Kyoto Encyclopedia Genes and Genomes (KEGG) and Mummichog pathway analysis. Results The two-way HCA 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]+ ), reduced FMN (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. Conclusion High resolution metabolomics (HRM) is a promising approach in asthma research. Five candidate markers were identified to be related to CS resistant severe asthmatic children. These compounds, upon validation, may contribute further in the understanding of CS resistance among severe asthmatics through the use of urine.