Elevated vanillylmandelate and sphingomyelins were associated with lower baseline FEV1 and faster longitudinal FEV1 decline in patients with COPD across two large cohorts.
Cohort (n=13,625)
Yes
Metabolomic profiling identifies catecholamine, sphingolipid, and amino acid metabolism pathways as key markers of spirometric progression in COPD.
Abstract Rationale Chronic Obstructive Pulmonary Disease (COPD) is a progressive, heterogeneous disorder characterized by airflow limitation and systemic manifestations. Molecular predictors of disease progression remain poorly defined. Circulating metabolites, reflecting host-environment interactions, may reveal biochemical mechanisms underlying COPD pathogenesis and progression. We evaluated plasma metabolomic signatures of lung function and its decline in COPD. Methods We analyzed baseline (Visit 1) and longitudinal (Visit 5) spirometry and plasma metabolomic data from SPIROMICS (n = 2,973) and COPDGene (n = 10,652). Analyses included baseline (SPIROMICS n = 2,471; COPDGene n = 914) and follow-up (SPIROMICS n = 799; COPDGene n = 1,962) samples profiled on the Metabolon platform. Metabolites with 20% missingness were imputed using k-nearest neighbors (k = 10); those with 80% missingness were excluded. Intensities were log-transformed. Within each cohort, multivariable linear regression models assessed:(1) baseline post-bronchodilator FEV1 vs. metabolite levels, and(2) longitudinal change in FEV1 (ΔFEV1) vs. change in metabolite levels (ΔMetabolite),adjusted for age, sex, race, BMI, smoking status, pack-years, exacerbation history, and site. Multiple testing correction used Benjamini-Hochberg FDR 0.05 for baseline and nominal P 0.05 for longitudinal analyses. Pathway enrichment used MetaboAnalyst with KEGG annotations. Results Cross-sectionally, vanillylmandelate (VMA), X-13553, and sphingomyelins were negatively associated with FEV1 in SPIROMICS. In COPDGene, VMA and C-glycosyltryptophan showed similar negative associations, while androstenediol sulfates (DHEA-S) were positively associated.Longitudinally, increases in sphingomyelins (d18:2/23:1, d18:2/24:2) and VMA in SPIROMICS, and higher glycochenodeoxycholate glucuronide, 4-hydroxyhippurate, and N-acetylglycine in COPDGene, were linked to faster FEV1 decline. Histidine, metabolonic lactone sulfate, and taurodeoxycholate were inversely associated with decline. Conclusions Metabolomic profiling across two large COPD cohorts identifies catecholamine, sphingolipid, and amino acid metabolism as key pathways underlying spirometric progression. Elevated VMA suggests catecholaminergic stress and oxidative imbalance, while lipid remodeling and amino acid-derived antioxidants indicate compensatory responses. These findings support metabolomics as a framework to identify aging-related biomarkers and therapeutic targets in chronic lung disease. Figure 1. Cross-sectional and longitudinal metabolite associations with lung function in SPIROMICS and COPDGene. Panels A-B: Baseline post-bronchodilator FEV1 vs. plasma metabolites in SPIROMICS (A) and COPDGene (B).Panels C-D: Change in FEV1 (ΔFEV1) vs. change in metabolites (ΔMetabolite) in SPIROMICS (C) and COPDGene (D). This abstract is funded by: NIH
Nasirpour et al. (Fri,) conducted a cohort in Chronic Obstructive Pulmonary Disease (COPD) (n=13,625). Plasma metabolomic signatures was evaluated on Baseline post-bronchodilator FEV1 and longitudinal change in FEV1 (ΔFEV1). Elevated vanillylmandelate and sphingomyelins were associated with lower baseline FEV1 and faster longitudinal FEV1 decline in patients with COPD across two large cohorts.
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