title: Plasma sphingolipids associated with chronic obstructive pulmonary disease phenotypes.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: 1 National Jewish Health, Denver, Colorado.
authors.forename: Russell P
authors.initials: RP
authors.lastname: Bowler
authors.forename: Sean
authors.initials: S
authors.lastname: Jacobson
authors.forename: Charmion
authors.initials: C
authors.lastname: Cruickshank
authors.forename: Grant J
authors.initials: GJ
authors.lastname: Hughes
authors.forename: Charlotte
authors.initials: C
authors.lastname: Siska
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Ory
authors.forename: Irina
authors.initials: I
authors.lastname: Petrache
authors.forename: Jean E
authors.initials: JE
authors.lastname: Schaffer
authors.forename: Nichole
authors.initials: N
authors.lastname: Reisdorph
authors.forename: Katerina
authors.initials: K
authors.lastname: Kechris
mesh_terms: D015415:Biomarkers / Q000097:blood; D005786:Gene Expression Regulation; D006028:Glycosphingolipids / Q000097:blood*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D013058:Mass Spectrometry; D010641:Phenotype; D011237:Predictive Value of Tests; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood* / Q000175:diagnosis*; D011656:Pulmonary Emphysema / Q000097:blood / Q000175:diagnosis; D012307:Risk Factors; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D012907:Smoking / Q000009:adverse effects; D013109:Sphingomyelins / Q000097:blood; D014281:Trihexosylceramides / Q000097:blood
chemical_list: D015415:Biomarkers; D006028:Glycosphingolipids; D013109:Sphingomyelins; D014281:Trihexosylceramides; C012905:dihexosylceramide
keywords: ceramides; emphysema; genomics; metabolomics; sphingomyelins