Plasma sphingolipids associated with chronic obstructive pulmonary disease phenotypes

Russell P. Bowler, Sean Jacobson, Charmion Cruickshank, Grant J. Hughes, Charlotte Siska, Daniel S. Ory, Irina Petrache, Jean E. Schaffer, Nichole Reisdorph, Katerina Kechris

Research output: Contribution to journalArticle

60 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)275-284
Number of pages10
JournalAmerican journal of respiratory and critical care medicine
Volume191
Issue number3
DOIs
StatePublished - Feb 1 2015

Keywords

  • Ceramides
  • Emphysema
  • Genomics
  • Metabolomics
  • Sphingomyelins

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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    Bowler, R. P., Jacobson, S., Cruickshank, C., Hughes, G. J., Siska, C., Ory, D. S., Petrache, I., Schaffer, J. E., Reisdorph, N., & Kechris, K. (2015). Plasma sphingolipids associated with chronic obstructive pulmonary disease phenotypes. American journal of respiratory and critical care medicine, 191(3), 275-284. https://doi.org/10.1164/rccm.201410-1771OC