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

Ivana Prokić; Lies Lahousse; Maaike de Vries; Jun Liu; Marita Kalaoja; Judith M Vonk; Diana A van der Plaat; Cleo C van Diemen; Ashley van der Spek; Alexandra Zhernakova; Jingyuan Fu; Mohsen Ghanbari; Mika Ala-Korpela; Johannes Kettunen; Aki S Havulinna; Markus Perola; Veikko Salomaa; Lars Lind; Johan Ärnlöv; Bruno H C Stricker; Guy G Brusselle; H Marike Boezen; Cornelia M van Duijn; Najaf Amin

doi:10.1186/s12890-020-01222-7

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

Ivana Prokić^*, Lies Lahousse, Maaike de Vries, Jun Liu, Marita Kalaoja, Judith M Vonk, Diana A van der Plaat, Cleo C van Diemen, Ashley van der Spek, Alexandra Zhernakova, Jingyuan Fu, Mohsen Ghanbari, Mika Ala-Korpela, Johannes Kettunen, Aki S Havulinna, Markus Perola, Veikko Salomaa, Lars Lind, Johan Ärnlöv, Bruno H C StrickerGuy G Brusselle, H Marike Boezen, Cornelia M van Duijn, Najaf Amin

^*Corresponding author for this work

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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.

Original language	English
Article number	193
Number of pages	10
Journal	BMC Pulmonary Medicine
Volume	20
Issue number	1
DOIs	https://doi.org/10.1186/s12890-020-01222-7
Publication status	Published - 16-Jul-2020

Keywords

COPD
Metabolomics
Mendelian randomization
Glycoprotein acetyls
Biomarkers
ACUTE-PHASE PROTEINS
LUNG-FUNCTION
RISK-FACTORS
GLYCOPROTEIN
MORTALITY
BIOMARKER
IDENTIFY
TESTS
GLYCA
LOCI

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Additional file 1 of A cross-omics integrative study of metabolic signatures of chronic obstructive pulmonary disease
Ghanbari, M. (Contributor), Salomaa, V. (Contributor), Havulinna, A. S. (Contributor), van Diemen, C. (Contributor), Stricker, B. H. C. (Contributor), Lind, L. (Contributor), Liu, J. (Contributor), Lahousse, L. (Contributor), Perola, M. (Contributor), Van Der Spek, A. (Contributor), Vonk, J. M. (Contributor), Äarnlöv, J. (Contributor), Kalaoja, M. (Contributor), Kettunen, J. (Contributor), Boezen, H. (Contributor), Yang-Fu, J. (Contributor), de Vries, M. (Contributor), Zhernakova, S. (Contributor), Amin, N. (Contributor), Plaat ,van der, D. (Contributor), Ala-Korpela, M. (Contributor), Prokić, I. (Contributor), Brusselle, G. G. (Contributor) & Van Duijn, C. M. (Contributor), University of Groningen, 1-Jan-2020
DOI: 10.6084/m9.figshare.12667566.v1
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Prokić, I., Lahousse, L., de Vries, M., Liu, J., Kalaoja, M., Vonk, J. M., van der Plaat, D. A., van Diemen, C. C., van der Spek, A., Zhernakova, A., Fu, J., Ghanbari, M., Ala-Korpela, M., Kettunen, J., Havulinna, A. S., Perola, M., Salomaa, V., Lind, L., Ärnlöv, J., ... Amin, N. (2020). A cross-omics integrative study of metabolic signatures of chronic obstructive pulmonary disease. BMC Pulmonary Medicine, 20(1), Article 193. https://doi.org/10.1186/s12890-020-01222-7

@article{7c59c47e3f2b4818b307d87568545f92,

title = "A cross-omics integrative study of metabolic signatures of chronic obstructive pulmonary disease",

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 = "COPD, Metabolomics, Mendelian randomization, Glycoprotein acetyls, Biomarkers, ACUTE-PHASE PROTEINS, LUNG-FUNCTION, RISK-FACTORS, GLYCOPROTEIN, MORTALITY, BIOMARKER, IDENTIFY, TESTS, GLYCA, LOCI",

author = "Ivana Proki{\'c} and Lies Lahousse and {de Vries}, Maaike and Jun Liu and Marita Kalaoja and Vonk, {Judith M} and {van der Plaat}, {Diana A} and {van Diemen}, {Cleo C} and {van der Spek}, Ashley and Alexandra Zhernakova and Jingyuan Fu and Mohsen Ghanbari and Mika Ala-Korpela and Johannes Kettunen and Havulinna, {Aki S} and Markus Perola and Veikko Salomaa and Lars Lind and Johan {\"A}rnl{\"o}v and Stricker, {Bruno H C} and Brusselle, {Guy G} and Boezen, {H Marike} and {van Duijn}, {Cornelia M} and Najaf Amin",

year = "2020",

month = jul,

day = "16",

doi = "10.1186/s12890-020-01222-7",

language = "English",

volume = "20",

journal = "BMC Pulmonary Medicine",

issn = "1471-2466",

publisher = "BioMed Central Ltd.",

number = "1",

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Prokić, I, Lahousse, L, de Vries, M, Liu, J, Kalaoja, M, Vonk, JM, van der Plaat, DA, van Diemen, CC, van der Spek, A, Zhernakova, A , Fu, J, Ghanbari, M, Ala-Korpela, M, Kettunen, J, Havulinna, AS, Perola, M, Salomaa, V, Lind, L, Ärnlöv, J, Stricker, BHC, Brusselle, GG, Boezen, HM, van Duijn, CM & Amin, N 2020, 'A cross-omics integrative study of metabolic signatures of chronic obstructive pulmonary disease', BMC Pulmonary Medicine, vol. 20, no. 1, 193. https://doi.org/10.1186/s12890-020-01222-7

TY - JOUR

T1 - A cross-omics integrative study of metabolic signatures of chronic obstructive pulmonary disease

AU - Prokić, Ivana

AU - Lahousse, Lies

AU - de Vries, Maaike

AU - Liu, Jun

AU - Kalaoja, Marita

AU - Vonk, Judith M

AU - van der Plaat, Diana A

AU - van Diemen, Cleo C

AU - van der Spek, Ashley

AU - Zhernakova, Alexandra

AU - Fu, Jingyuan

AU - Ghanbari, Mohsen

AU - Ala-Korpela, Mika

AU - Kettunen, Johannes

AU - Havulinna, Aki S

AU - Perola, Markus

AU - Salomaa, Veikko

AU - Lind, Lars

AU - Ärnlöv, Johan

AU - Stricker, Bruno H C

AU - Brusselle, Guy G

AU - Boezen, H Marike

AU - van Duijn, Cornelia M

AU - Amin, Najaf

PY - 2020/7/16

Y1 - 2020/7/16

N2 - 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.

AB - 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.

KW - COPD

KW - Metabolomics

KW - Mendelian randomization

KW - Glycoprotein acetyls

KW - Biomarkers

KW - ACUTE-PHASE PROTEINS

KW - LUNG-FUNCTION

KW - RISK-FACTORS

KW - GLYCOPROTEIN

KW - MORTALITY

KW - BIOMARKER

KW - IDENTIFY

KW - TESTS

KW - GLYCA

KW - LOCI

U2 - 10.1186/s12890-020-01222-7

DO - 10.1186/s12890-020-01222-7

M3 - Article

C2 - 32677943

SN - 1471-2466

VL - 20

JO - BMC Pulmonary Medicine

JF - BMC Pulmonary Medicine

IS - 1

M1 - 193

ER -

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

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Additional file 1 of A cross-omics integrative study of metabolic signatures of chronic obstructive pulmonary disease

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