Afshan Masood1, Minnie Jacob2, Xinyun Gu3, Mai Abdel Jabar3, Hicham Benabdelkamel1, Imran Nizami4, Liang Li3, Majed Dasouki2, Anas M Abdel Rahman5,6,7. 1. Proteomics Resource Unit, Obesity Research Center, College of Medicine, King Saud University, PO. Box 2925 (98), Riyadh, 11461, Saudi Arabia. 2. Metabolomics Section, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), Zahrawi Street, Al Maather, PO. Box 3354, Riyadh, 11211, Saudi Arabia. 3. Department of Chemistry, University of Alberta, Edmonton, AB, T6G 2R3, Canada. 4. Lung Transplant Section, Organ Transplant Center, King Faisal Specialist Hospital and Research Center, Zahrawi Street, Al Maather, Riyadh, 11211, Saudi Arabia. 5. Metabolomics Section, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), Zahrawi Street, Al Maather, PO. Box 3354, Riyadh, 11211, Saudi Arabia. aabdelrahman46@kfshrc.edu.sa. 6. Department of Biochemistry and Molecular Medicine, College of Medicine, Al Faisal University, Riyadh, Saudi Arabia. aabdelrahman46@kfshrc.edu.sa. 7. Department of Chemistry, Memorial University of Newfoundland, St. John's, NL, A1B 3X7, Canada. aabdelrahman46@kfshrc.edu.sa.
Abstract
INTRODUCTION: Cystic fibrosis (CF) is a lethal multisystemic disease of a monogenic origin with numerous mutations. Functional defects in the cystic fibrosis transmembrane conductance receptor (CFTR) protein based on these mutations are categorised into distinct classes having different clinical presentations and disease severity. OBJECTIVES: The present study aimed to create a comprehensive metabolomic profile of altered metabolites in patients with CF, among different classes and in relation to lung function. METHODS: A chemical isotope labeling liquid chromatography-mass spectrometry metabolomics was used to study the serum metabolic profiles of young and adult CF (n = 39) patients and healthy controls (n = 30). Comparisons were made at three levels, CF vs. controls, among mutational classes of CF, between CF class III and IV, and correlated the lung function findings. RESULTS: A distinctive metabolic profile was observed in the three analyses. 78, 20, and 13 significantly differentially dysregulated metabolites were identified in the patients with CF, among the different classes and between class III and IV, respectively. The significantly identified metabolites included amino acids, di-, and tri-peptides, glutathione, glutamine, glutamate, and arginine metabolism. The top significant metabolites include 1-Aminopropan-2-ol, ophthalmate, serotonin, cystathionine, and gamma-glutamylglutamic acid. Lung function represented by an above-average FEV1% level was associated with decreased glutamic acid and increased guanosine levels. CONCLUSION: Metabolomic profiling identified alterations in different amino acids and dipeptides, involved in regulating glutathione metabolism. Two metabolites, 3,4-dihydroxymandelate-3-O-sulfate and 5-Aminopentanoic acid, were identified in common between the three anlayses and may represent as highly sensitive biomarkers for CF.
INTRODUCTION:Cystic fibrosis (CF) is a lethal multisystemic disease of a monogenic origin with numerous mutations. Functional defects in the cystic fibrosis transmembrane conductance receptor (CFTR) protein based on these mutations are categorised into distinct classes having different clinical presentations and disease severity. OBJECTIVES: The present study aimed to create a comprehensive metabolomic profile of altered metabolites in patients with CF, among different classes and in relation to lung function. METHODS: A chemical isotope labeling liquid chromatography-mass spectrometry metabolomics was used to study the serum metabolic profiles of young and adult CF (n = 39) patients and healthy controls (n = 30). Comparisons were made at three levels, CF vs. controls, among mutational classes of CF, between CF class III and IV, and correlated the lung function findings. RESULTS: A distinctive metabolic profile was observed in the three analyses. 78, 20, and 13 significantly differentially dysregulated metabolites were identified in the patients with CF, among the different classes and between class III and IV, respectively. The significantly identified metabolites included amino acids, di-, and tri-peptides, glutathione, glutamine, glutamate, and arginine metabolism. The top significant metabolites include 1-Aminopropan-2-ol, ophthalmate, serotonin, cystathionine, and gamma-glutamylglutamic acid. Lung function represented by an above-average FEV1% level was associated with decreased glutamic acid and increased guanosine levels. CONCLUSION: Metabolomic profiling identified alterations in different amino acids and dipeptides, involved in regulating glutathione metabolism. Two metabolites, 3,4-dihydroxymandelate-3-O-sulfate and 5-Aminopentanoic acid, were identified in common between the three anlayses and may represent as highly sensitive biomarkers for CF.
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Authors: C Castellani; H Cuppens; M Macek; J J Cassiman; E Kerem; P Durie; E Tullis; B M Assael; C Bombieri; A Brown; T Casals; M Claustres; G R Cutting; E Dequeker; J Dodge; I Doull; P Farrell; C Ferec; E Girodon; M Johannesson; B Kerem; M Knowles; A Munck; P F Pignatti; D Radojkovic; P Rizzotti; M Schwarz; M Stuhrmann; M Tzetis; J Zielenski; J S Elborn Journal: J Cyst Fibros Date: 2008-05 Impact factor: 5.482
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