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Distinctive metabolic profiles between Cystic Fibrosis mutational subclasses and lung function

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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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Authors and Affiliations

  1. Proteomics Resource Unit, Obesity Research Center, College of Medicine, King Saud University, PO. Box 2925 (98), Riyadh, 11461, Saudi Arabia

    Afshan Masood & Hicham Benabdelkamel

  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

    Minnie Jacob, Majed Dasouki & Anas M. Abdel Rahman

  3. Department of Chemistry, University of Alberta, Edmonton, AB, T6G 2R3, Canada

    Xinyun Gu, Mai Abdel Jabar & Liang Li

  4. Lung Transplant Section, Organ Transplant Center, King Faisal Specialist Hospital and Research Center, Zahrawi Street, Al Maather, Riyadh, 11211, Saudi Arabia

    Imran Nizami

  5. Department of Biochemistry and Molecular Medicine, College of Medicine, Al Faisal University, Riyadh, Saudi Arabia

    Anas M. Abdel Rahman

  6. Department of Chemistry, Memorial University of Newfoundland, St. John’s, NL, A1B 3X7, Canada

    Anas M. Abdel Rahman

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  1. Afshan Masood
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  2. Minnie Jacob
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  3. Xinyun Gu
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  4. Mai Abdel Jabar
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  5. Hicham Benabdelkamel
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  6. Imran Nizami
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  7. Liang Li
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  8. Majed Dasouki
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  9. Anas M. Abdel Rahman
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Contributions

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.

Corresponding author

Correspondence to Anas M. Abdel Rahman.

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The authors declare that all the patients who participated in this study provided informed consent to use their biological material.

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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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