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.
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Abbreviations
- CF:
-
Cystic Fibrosis
- CFTR:
-
Cystic Fibrosis Transmembrane Conductance Regulator
- ROS:
-
Reactive Oxygen Species
- VOC:
-
Volatile Organic Compounds
- DBS:
-
Dried Blood Spots
- GC–MS:
-
Gas Chromatography-Mass Spectrometry
- CIL LC–MS:
-
Chemical isotope labeling liquid chromatography-mass spectrometry
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Acknowledgements
The authors would like to express their gratitude to the Executive Director of the Research Centre, King Faisal Specialist Hospital and Research Centre, to Dr. Brian Meyer, Chairman of the Department of Genetics, for the funding supports, and to all the patients who contributed to this project. The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for funding this research through the Research Group Project no. RGP-334. The work performed at the Li-node of the Metabolomics Innovation Centre (TMIC) of Canada was partially funded by Genome Canada and Canada Foundation for Innovation.
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AM analyzed the data and wrote the first draft of the manuscript. MJ compiled the figures and tables and contributed to drafting the manuscript. LL and XG conducted the metabolomics experiment, IN and MAJ recruited patients and provided their clinical data and samples. HB performed the proteomics analysis. MD critically revised the manuscript, and AMAR designed the study, supervised experiments, data analysis, and finalized the manuscript. All authors approved the final version of the manuscript.
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Masood, A., Jacob, M., Gu, X. et al. Distinctive metabolic profiles between Cystic Fibrosis mutational subclasses and lung function. Metabolomics 17, 4 (2021). https://doi.org/10.1007/s11306-020-01760-5
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DOI: https://doi.org/10.1007/s11306-020-01760-5