Metabolomics analysis identifies sex-associated metabotypes of oxidative stress and the autotaxin–lysoPA axis in COPD

Naz, Saima; Kolmert, Johan; Yang, Mingxing; Reinke, Stacey N.; Kamleh, Muhammad Anas; Snowden, Stuart G.; Heyder, Tina; Levänen, Bettina; Erle, David J.; Sköld, C. Magnus; Wheelock, Åsa M.; Wheelock, Craig E.

doi:10.1183/13993003.02322-2016

Cited by 78 publications

(93 citation statements)

References 52 publications

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“…Nine omics data blocks (figure 1) from 52 female subjects (20 Healthy,20 Smokers, 12 COPD) were used: mRNA from BAL cells collected by microarray [22]; miRNA from BAL cells and from exosomes from BAL fluid (BALF) collected by microarray [22,27]; difference gel electrophoresis (DIGE) proteomics from BAL cells [17]; shotgun proteomics data from BAL cells collected by isobaric tags for relative and absolute quantitation (iTRAQ) mass spectrometry (MS) [25,28]; shotgun proteomics data from BEC collected by means of tandem mass tag (TMT)-MS [29]; eicosanoid profiling data from serum and BALF [21]; and metabolomics data from serum [30]. For details regarding data collection platforms and data preprocessing, see previous publications and supplementary material.…”

Section: Omics Data Blocksmentioning

confidence: 99%

Integration of multi-omics datasets enables molecular classification of COPD

Wheelock

Sköld

et al. 2018

Eur Respir J

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Chronic obstructive pulmonary disease (COPD) is an umbrella diagnosis caused by a multitude of underlying mechanisms, and molecular sub-phenotyping is needed to develop molecular diagnostic/prognostic tools and efficacious treatments.The objective of these studies was to investigate whether multi-omics integration improves the accuracy of molecular classification of COPD in small cohorts.Nine omics data blocks (comprising mRNA, micro RNA, proteomes and metabolomes) collected from several anatomical locations from 52 female subjects were integrated by similarity network fusion (SNF). Multi-omics integration significantly improved the accuracy of group classification of COPD patients from healthy never-smokers and from smokers with normal spirometry, reducing required group sizes from n=30 to n=6 at 95% power. Seven different combinations of four to seven omics platforms achieved >95% accuracy.For the first time, a quantitative relationship between multi-omics data integration and accuracy of data-driven classification power has been demonstrated across nine omics data blocks. Integrating five to seven omics data blocks enabled 100% correct classification of COPD diagnosis with groups as small as n=6 individuals, despite strong confounding effects of current smoking. These results can serve as guidelines for the design of future systems-based multi-omics investigations, with indications that integrating five to six data blocks from several molecular levels and anatomical locations suffices to facilitate unsupervised molecular classification in small cohorts.

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Section: Omics Data Blocksmentioning

confidence: 99%

Integration of multi-omics datasets enables molecular classification of COPD

Wheelock

Sköld

et al. 2018

Eur Respir J

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“…These studies also support a hypothesis of FA oxidation and tryptophan metabolism dysregulation leading to a state of high oxidative stress. An effect on FA oxidation was also demonstrated in COPD participants by Naz et al who measured the ratio of carnitine and acylcarnitine using tandem LC–MS. The study found that the ratios between the medium‐ and long‐chain carnitines were significantly lower in the COPD samples compared to the healthy controls.…”

Section: Metabolomic‐driven Discovery Of Biomarkersmentioning

confidence: 64%

“…A number of recent studies have revealed metabolic dysregulation in COPD patients . For example, alterations in the sphingolipid metabolism was identified in COPD patients and patients in the Karolinska smoking‐related disease cohort, suggesting a dysregulation of lipid metabolism during the onset of COPD. This was further supported by the findings of Adamko et al who identified an increase in betaine and choline levels in COPD patients.…”

Section: Metabolomic‐driven Discovery Of Biomarkersmentioning

confidence: 99%

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Metabolomics in chronic lung diseases

et al. 2019

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Chronic lung diseases represent a significant global burden. Their increasing incidence and complexity render a comprehensive, multidisciplinary and personalized approach to each patient, critically important. Most recently, unique biochemical pathways and disease markers have been identified through large‐scale metabolomic studies. Metabolomics is the study of metabolic pathways and the measurement of unique biomolecules in a living system. Analysing samples from different compartments such as bronchoalveolar lavage fluid (BALF) and plasma has proven useful for the characterization of a number of pathological conditions and offers promise as a clinical tool. For example, several studies using mass spectrometry (MS) have shown alterations in the sphingolipid metabolism of chronic obstructive pulmonary disease (COPD) sufferers. In this article, we present a practical review of the application of metabolomics to the study of chronic lung diseases (CLD): COPD, idiopathic pulmonary fibrosis (IPF) and asthma. The insights, which the analytical strategies employed in metabolomics, have provided to the dissection of the biochemistry of CLD and future clinical biomarkers are explored.

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“…(COSMIC) cohort: The Karolinska COSMIC cohort (Clinical Trials ID: NCT02627872) is a cross-sectional study designed for investigating the molecular pathogenesis of COPD. Methods of tissue procurement, cohort characteristics, and gene expression profiling have been previously described and further details are provided in Supplementary Methods (18,44). MicroRNA profiling was performed on airway epithelial brushings collected by fiberoptic bronchoscopy in a subset of the Karolinska COSMIC cohort.…”

Section: Clinical and Systems Medicine Investigations Of Smoking-relatementioning

confidence: 99%

Decreased miR-24-3p potentiates DNA damage responses and increases susceptibility to COPD

Nouws

Wan

Finnemore

et al. 2020

Preprint

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COI: EF is currently employed by Rubius Therapeutics; VN is currently employed by Akoya Bioscience; RB is cofounder and consultant for Cybrexa Therapeutics; MS and PJL are co-inventors on a pending patent describing the therapeutic utility of MIF020 in lung disease; NK reports personal fees from Biogen Idec, Boehringer Ingelheim, Third Rock, Miragen, Pliant, Samumed, NuMedii, Indaloo, Theravance, LifeMax, Optikira, Three Lake Partners and has filed patents related to the use of thyroid hormone as an antifibrotic agent and novel biomarkers in pulmonary fibrosis. ABSTRACTActivation of the DNA damage response (DDR) due to chronic exposure to cigarette smoke (CS) is implicated in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). However, not all smokers develop COPD and the pathologic consequences of CS exposure are heterogenous. Cellular mechanisms that regulate the DDR and contribute to disease progression in susceptible individuals are poorly understood. Because microRNAs are well known regulators of the DDR, we evaluated microRNA expression arrays performed on lung samples from 172 subjects with and without COPD. We identified miR-24-3p as the microRNA best correlated with radiographic emphysema (ρ=-0.353, P=1.3e-04) and validated this finding in multiple cohorts.In a CS-exposure mouse model, miR-24-3p inhibition increased emphysema severity. In human airway epithelial cells, miR-24-3p suppressed apoptosis through the BH3-only protein BIM and suppressed homologydirected DNA repair and the DNA repair protein BRCA1. Finally, we found BIM and BRCA1 were increased in COPD lung tissue and inversely correlated with miR-24-3p expression. We concluded that decreased miR-24-3p expression increases COPD susceptibility and potentiates the DDR through BIM and BRCA1.

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Metabolomics analysis identifies sex-associated metabotypes of oxidative stress and the autotaxin–lysoPA axis in COPD

Cited by 78 publications

References 52 publications

Integration of multi-omics datasets enables molecular classification of COPD

Integration of multi-omics datasets enables molecular classification of COPD

Metabolomics in chronic lung diseases

Decreased miR-24-3p potentiates DNA damage responses and increases susceptibility to COPD

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