Metabolomic Profiling Reveals Sex Specific Associations with Chronic Obstructive Pulmonary Disease and Emphysema

Gillenwater, Lucas A.; Kechris, Katerina; Pratte, Katherine; Reisdorph, Nichole; Petrache, Irina; Labaki, Wassim W.; O’Neal, Wanda K.; Krishnan, Jerry A.; Ortega, Victor E.; DeMeo, Dawn L.; Bowler, Russell P.

doi:10.3390/metabo11030161

Cited by 19 publications

(34 citation statements)

References 64 publications

(80 reference statements)

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“…Similar to the large population cohort studies described above, Kim et al [ 4 ], used liquid chromatography and mass spectrometry (LC-MS) on serum and urine samples in a study of 59 TB-related COPD patients, 70 smoking-related COPD patients, and 39 healthy controls (including never-smokers and smokers) and found differences in the acylcarnitines. Similar results were shown in a COPDGene discovery cohort of 839 and a SPIROMICS replication cohort of 446 using LC-MS on serum samples [ 14 ]. The differences in carnitines in COPDGene and SPIROMICS were more pronounced in women compared to men.…”

Section: Resultssupporting

confidence: 82%

Metabolome Features of COPD: A Scoping Review

Godbole

Bowler

2022

Metabolites

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Chronic obstructive pulmonary disease (COPD) is a complex heterogeneous disease state with multiple phenotypic presentations that include chronic bronchitis and emphysema. Although COPD is a lung disease, it has systemic manifestations that are associated with a dysregulated metabolome in extrapulmonary compartments (e.g., blood and urine). In this scoping review of the COPD metabolomics literature, we identified 37 publications with a primary metabolomics investigation of COPD phenotypes in human subjects through Google Scholar, PubMed, and Web of Science databases. These studies consistently identified a dysregulation of the TCA cycle, carnitines, sphingolipids, and branched-chain amino acids. Many of the COPD metabolome pathways are confounded by age and sex. The effects of COPD in young versus old and male versus female need further focused investigations. There are also few studies of the metabolome’s association with COPD progression, and it is unclear whether the markers of disease and disease severity are also important predictors of disease progression.

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Section: Resultssupporting

confidence: 82%

Metabolome Features of COPD: A Scoping Review

Godbole

Bowler

2022

Metabolites

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“…A nationwide prevalence study revealed that the prevalence of COPD in men is more than twice that of women (Fang et al, 2018). Recent studies also reported that the difference in metabolic profiles between male and female COPD patients (Gillenwater et al, 2021); (Naz et al, 2017). Therefore, lung tissue from male COPD patients in two independent set were collected to perform metabolomic analysis: a discovery set to detect and a replication set to validate.…”

Section: Discussionmentioning

confidence: 99%

Detection of the Disorders of Glycerophospholipids and Amino Acids Metabolism in Lung Tissue From Male COPD Patients

Huang

Wu²,

et al. 2022

Front. Mol. Biosci.

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Background: At present, few studies have reported the metabolic profiles of lung tissue in patients with COPD. Our study attempted to analyze the lung metabolome in male COPD patients and to screen the overlapping biomarkers of the lung and plasma metabolomes.Methods: We performed untargeted metabolomic analysis of normal lung tissue from two independent sets (the discovery set: 20 male COPD patients and 20 controls and the replication set: 47 male COPD patients and 27 controls) and of plasma samples from 80 male subjects containing 40 COPD patients and 40 controls.Results: We found glycerophospholipids (GPs) and Amino acids were the primary classes of differential metabolites between male COPD patients and controls. The disorders of GPs metabolism and the valine, leucine and isoleucine biosynthesis metabolism pathways were identified in lung discovery set and then also validated in the lung replication set. Combining lung tissue and plasma metabolome, Phytosphingosine and l-tryptophan were two overlapping metabolites biomarkers. Binary logistic regression suggested that phytosphingosine together with l-tryptophan was closely associated with male COPD and showed strong diagnostic power with an AUC of 0.911 (95% CI: 0.8460-0.9765).Conclusion: Our study revealed the metabolic perturbations of lung tissues from male COPD patients. The detected disorders of GPs and amino acids may provide an insight into the pathological mechanism of COPD. Phytosphingosine and l-tryptophan were two novel metabolic biomarkers for differentiating COPD patients and controls.

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“…P100 plasma was profiled using the Metabolon (Durham, NC, USA) Global Metabolomics platform. Briefly, untargeted liquid chromatography–tandem mass spectrometry (LC–MS/MS) was used to quantify 1392 metabolites and described in[ 62 , 63 ]. A data normalization step was performed to correct variation resulting from instrument inter-day tuning differences: metabolite intensities were divided by the metabolite run day median, then multiplied by the overall metabolite median.…”

Section: Methods and Modelsmentioning

confidence: 99%

PaIRKAT: A pathway integrated regression-based kernel association test with applications to metabolomics and COPD phenotypes

et al. 2021

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High-throughput data such as metabolomics, genomics, transcriptomics, and proteomics have become familiar data types within the “-omics” family. For this work, we focus on subsets that interact with one another and represent these “pathways” as graphs. Observed pathways often have disjoint components, i.e., nodes or sets of nodes (metabolites, etc.) not connected to any other within the pathway, which notably lessens testing power. In this paper we propose the Pathway Integrated Regression-based Kernel Association Test (PaIRKAT), a new kernel machine regression method for incorporating known pathway information into the semi-parametric kernel regression framework. This work extends previous kernel machine approaches. This paper also contributes an application of a graph kernel regularization method for overcoming disconnected pathways. By incorporating a regularized or “smoothed” graph into a score test, PaIRKAT can provide more powerful tests for associations between biological pathways and phenotypes of interest and will be helpful in identifying novel pathways for targeted clinical research. We evaluate this method through several simulation studies and an application to real metabolomics data from the COPDGene study. Our simulation studies illustrate the robustness of this method to incorrect and incomplete pathway knowledge, and the real data analysis shows meaningful improvements of testing power in pathways. PaIRKAT was developed for application to metabolomic pathway data, but the techniques are easily generalizable to other data sources with a graph-like structure.

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Metabolomic Profiling Reveals Sex Specific Associations with Chronic Obstructive Pulmonary Disease and Emphysema

Cited by 19 publications

References 64 publications

Metabolome Features of COPD: A Scoping Review

Metabolome Features of COPD: A Scoping Review

Detection of the Disorders of Glycerophospholipids and Amino Acids Metabolism in Lung Tissue From Male COPD Patients

PaIRKAT: A pathway integrated regression-based kernel association test with applications to metabolomics and COPD phenotypes

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