Plasma Sphingolipids Associated with Chronic Obstructive Pulmonary Disease Phenotypes

Abstract

Rationale: Chronic obstructive pulmonary disease (COPD) occurs in a minority of smokers and is characterized by intermittent exacerbations and clinical subphenotypes such as emphysema and chronic bronchitis. Although sphingolipids as a class are implicated in the pathogenesis of COPD, the particular sphingolipid species associated with COPD subphenotypes remain unknown.Objectives: To use mass spectrometry to determine which plasma sphingolipids are associated with subphenotypes of COPD.Methods: One hundred twenty-nine current and former smokers from the COPDGene cohort had 69 distinct sphingolipid species detected in plasma by targeted mass spectrometry. Of these, 23 were also measured in 131 plasma samples (117 independent subjects) using an untargeted platform in an independent laboratory. Regression analysis with adjustment for clinical covariates, correction for false discovery rate, and metaanalysis were used to test associations between COPD subphenotypes and sphingolipids. Peripheral blood mononuclear cells were used to test associations between sphingolipid gene expression and plasma sphingolipids.Measurements and Main Results: Of the measured plasma sphingolipids, five sphingomyelins were associated with emphysema; four trihexosylceramides and three dihexosylceramides were associated with COPD exacerbations. Three sphingolipids were strongly associated with sphingolipid gene expression, and 15 sphingolipid gene/metabolite pairs were differentially regulated between COPD cases and control subjects.Conclusions: There is evidence of systemic dysregulation of sphingolipid metabolism in patients with COPD. Subphenotyping suggests that sphingomyelins are strongly associated with emphysema and glycosphingolipids are associated with COPD exacerbations.

Metabolomics screening identifies reducedL-carnitine to be associated with progressive emphysema

“…scribed [15]. Although we saw no significant change in serum SM levels in our mouse model of emphysema, a number of SMs were significantly reduced during the progression of emphysema more local to the lung (Figure 2A).…”

“…To this end, there have been a number of studies published over the last few years assessing the COPD metabolome. This has included both untargeted [10][11][12][13] and targeted [14] metabolomics, as well as a combination of both [15] measured in either plasma or serum from COPD patients. In their combined approach, Bowler et al [15] reported a strong inverse association between the level of some plasma sphingomyelins (SMs) and emphysema in COPD patients.…”

“…This has included both untargeted [10][11][12][13] and targeted [14] metabolomics, as well as a combination of both [15] measured in either plasma or serum from COPD patients. In their combined approach, Bowler et al [15] reported a strong inverse association between the level of some plasma sphingomyelins (SMs) and emphysema in COPD patients. In addition to these clinical studies, one animal study used an untargeted approach to examine metabolomic changes in plasma following chronic exposure to cigarette smoke in a mouse model that resulted in emphysema [16] and a very recent study examining the effect of traditional Chinese medicine on a cigarette-smoke-induced rat model of COPD examined metabolite levels in lung tissue [17].…”

The discordant method: a novel approach for differential correlation

“…The peripheral blood mononuclear cell (PBMC) transcriptomic data was generated on the Affymetrix HGU133 Plus 2.0 array and normalized by measuring the geometric mean (Bahr et al, 2013). Metabolomic data from plasma was processed and generated using LC/MS Agilent software and tools and pre-processed and filtered using MSPrep (Bowler et al, 2015;Hughes et al, 2014). Both datasets were filtered based on Grubbs' outlier test, leaving 38 852 transcripts and 1640 metabolites (Grubbs' P-value > 0.05).…”

“…Previous studies by COPDGene have implicated sphingolipids and their related pathways in COPD (Bowler et al, 2015). Sphingolipid-related metabolites were determined using ID Browser in Mass Profiler Professional (MPP) software (Agilent).…”