A cross-omics integrative study of metabolic signatures of chronic obstructive pulmonary disease

Ivana Prokić¹, Lies Lahousse^{2

3}, Maaike de Vries^{4

5}, Jun Liu^{2

6}, Marita Kalaoja⁷, Judith M Vonk^{4

5}, Diana A van der Plaat^{4

5

8}, Cleo C van Diemen⁹, Ashley van der Spek², Alexandra Zhernakova⁹, Jingyuan Fu^{9

10}, Mohsen Ghanbari^{2

11}, Mika Ala-Korpela^{7

12}, Johannes Kettunen^{7

13}, Aki S Havulinna^{13

14}, Markus Perola^{13

14}, Veikko Salomaa¹³, Lars Lind¹⁵, Johan Ärnlöv^{16

17}, Bruno H C Stricker², Guy G Brusselle^{2

18

19}, H Marike Boezen^{4

5}, Cornelia M van Duijn^{2

6}, Najaf Amin^{2

6}

Affiliations

¹ Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. i.nedeljkovic@erasmusmc.nl.
² Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
³ Department of Bioanalysis, Pharmaceutical Care Unit, Ghent University, Ghent, Belgium.
⁴ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁵ Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁶ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁷ Computational Medicine department, Center for Life Course Health Research, Biocenter Oulu, University of Oulu, Oulu, Finland.
⁸ National Heart and Lung Institute, Imperial College London, London, UK.
⁹ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹⁰ Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹¹ Department of Genetics, School of Medicine,, Mashhad University of Medical Sciences, Mashhad, Iran.
¹² NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
¹³ Finnish Institute for Health and Welfare, Helsinki, Finland.
¹⁴ Molecular Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
¹⁵ Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
¹⁶ Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Huddinge, Sweden.
¹⁷ School of Health and Social Sciences, Dalarna University, Falun, Sweden.
¹⁸ Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
¹⁹ Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

PMID: 32677943
PMCID: PMC7364599
DOI: 10.1186/s12890-020-01222-7

A cross-omics integrative study of metabolic signatures of chronic obstructive pulmonary disease

Ivana Prokić et al. BMC Pulm Med. 2020.

. 2020 Jul 16;20(1):193.

doi: 10.1186/s12890-020-01222-7.

Authors

Affiliations

¹ Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. i.nedeljkovic@erasmusmc.nl.
² Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
³ Department of Bioanalysis, Pharmaceutical Care Unit, Ghent University, Ghent, Belgium.
⁴ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁵ Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁶ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁷ Computational Medicine department, Center for Life Course Health Research, Biocenter Oulu, University of Oulu, Oulu, Finland.
⁸ National Heart and Lung Institute, Imperial College London, London, UK.
⁹ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹⁰ Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹¹ Department of Genetics, School of Medicine,, Mashhad University of Medical Sciences, Mashhad, Iran.
¹² NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
¹³ Finnish Institute for Health and Welfare, Helsinki, Finland.
¹⁴ Molecular Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
¹⁵ Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
¹⁶ Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Huddinge, Sweden.
¹⁷ School of Health and Social Sciences, Dalarna University, Falun, Sweden.
¹⁸ Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
¹⁹ Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

PMID: 32677943
PMCID: PMC7364599
DOI: 10.1186/s12890-020-01222-7

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is a common lung disorder characterized by persistent and progressive airflow limitation as well as systemic changes. Metabolic changes in blood may help detect COPD in an earlier stage and predict prognosis.

Methods: We conducted a comprehensive study of circulating metabolites, measured by proton Nuclear Magnetic Resonance Spectroscopy, in relation with COPD and lung function. The discovery sample consisted of 5557 individuals from two large population-based studies in the Netherlands, the Rotterdam Study and the Erasmus Rucphen Family study. Significant findings were replicated in 12,205 individuals from the Lifelines-DEEP study, FINRISK and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) studies. For replicated metabolites further investigation of causality was performed, utilizing genetics in the Mendelian randomization approach.

Results: There were 602 cases of COPD and 4955 controls used in the discovery meta-analysis. Our logistic regression results showed that higher levels of plasma Glycoprotein acetyls (GlycA) are significantly associated with COPD (OR = 1.16, P = 5.6 × 10^{- 4} in the discovery and OR = 1.30, P = 1.8 × 10^{- 6} in the replication sample). A bi-directional two-sample Mendelian randomization analysis suggested that circulating blood GlycA is not causally related to COPD, but that COPD causally increases GlycA levels. Using the prospective data of the same sample of Rotterdam Study in Cox-regression, we show that the circulating GlycA level is a predictive biomarker of COPD incidence (HR = 1.99, 95%CI 1.52-2.60, comparing those in the highest and lowest quartile of GlycA) but is not significantly associated with mortality in COPD patients (HR = 1.07, 95%CI 0.94-1.20).

Conclusions: Our study shows that circulating blood GlycA is a biomarker of early COPD pathology.

Keywords: Biomarkers; COPD; Glycoprotein acetyls; Mendelian randomization; Metabolomics.

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Conflict of interest statement

All authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. VS has participated in a conference trip sponsored by Novo Nordisk and received a modest honorarium from the same source for participating in an advisory board meeting. He also has ongoing research collaboration with Bayer Ltd.

Figures

**Fig. 1**
Top metabolites associated with COPD and/or FEV₁/FVC. Colors represent standardized effect estimates of the metabolite association with corresponding trait (COPD, FEV₁/FVC). Red color means that the trait is associated with a higher metabolite concentration, while blue represents a lower metabolite concetration. For replicated metabolites, replication P-value is shown with stars: *P < 0.05 and ***P < 0.001. HDL – high-density lipoprotein

See this image and copyright information in PMC

References

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A cross-omics integrative study of metabolic signatures of chronic obstructive pulmonary disease

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A cross-omics integrative study of metabolic signatures of chronic obstructive pulmonary disease

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