Abstract
BackgroundChronic 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.MethodsWe 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.ResultsThere 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).ConclusionsOur study shows that circulating blood GlycA is a biomarker of early COPD pathology.
Highlights
Chronic obstructive pulmonary disease (COPD) is a common lung disorder characterized by persistent and progressive airflow limitation as well as systemic changes
Exploring causality of the association between COPD and metabolites We have used a bi-directional approach in which we examined whether: 1) the genetic determinants of the significant metabolites are associated with COPD and lung function, which would lead to the conclusion that the metabolites are most likely driving the disease; 2) the genetic determinants of COPD are associated with significant metabolites when the metabolites would most likely be altered as an integral part of the disease pathophysiology and may be biomarkers
Since FINRISK97 and DILGOM studies are based on the data from National health registers, and do not have minimum age entry criteria, the percentage of COPD cases is lower compared with discovery sample, containing elderly population
Summary
Chronic obstructive pulmonary disease (COPD) is a common lung disorder characterized by persistent and progressive airflow limitation as well as systemic changes. Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease and currently the third leading cause of death worldwide [1, 2]. COPD is a complex heterogeneous disease in which systemic features beyond airflow obstruction, including systemic inflammation, oxidative stress, muscle dysfunction, cachexia and vascular pathology occur [5, 6]. Understanding these systemic effects may give new insights into the pathogenesis and progression of COPD but may alternatively yield important clues for preventive research
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