Peripheral blood mononuclear cell gene expression in chronic obstructive pulmonary disease.

Abstract

Although most cases of chronic obstructive pulmonary disease (COPD) occur in smokers, only a fraction of smokers develop the disease. We hypothesized distinct molecular signatures for COPD and emphysema in the peripheral blood mononuclear cells (PBMCs) of current and former smokers. To test this hypothesis, we identified and validated PBMC gene expression profiles in smokers with and without COPD. We generated expression data on 136 subjects from the COPDGene study, using Affymetrix U133 2.0 microarrays (Affymetrix, Santa Clara, CA). Multiple linear regression with adjustment for covariates (gender, age, body mass index, family history, smoking status, and pack-years) was used to identify candidate genes, and ingenuity pathway analysis was used to identify candidate pathways. Candidate genes were validated in 149 subjects according to multiplex quantitative real-time polymerase chain reaction, which included 75 subjects not previously profiled. Pathways that were differentially expressed in subjects with COPD and emphysema included those that play a role in the immune system, inflammatory responses, and sphingolipid (ceramide) metabolism. Twenty-six of the 46 candidate genes (e.g., FOXP1, TCF7, and ASAH1) were validated in the independent cohort. Plasma metabolomics was used to identify a novel glycoceramide (galabiosylceramide) as a biomarker of emphysema, supporting the genomic association between acid ceramidase (ASAH1) and emphysema. COPD is a systemic disease whose gene expression signatures in PBMCs could serve as novel diagnostic or therapeutic targets.

• Authors: Timothy M Bahr, Grant J Hughes, Michael Armstrong, Rick Reisdorph, Christopher D Coldren, Michael G Edwards, Christina Schnell, Ross Kedl, Daniel J LaFlamme, Nichole Reisdorph, Katerina J Kechris, Russell P Bowler
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 49 Issue 2 Pg. 316-23 (Aug 2013) ISSN: 1535-4989 [Electronic] United States
• PMID: 23590301 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Gangliosides
• galabiosylceramide

Topics

• Aged
• Aged, 80 and over
• Biomarkers (blood)
• Female
• Gangliosides (blood)
• Gene Expression Regulation
• Humans
• Leukocytes, Mononuclear (metabolism)
• Male
• Metabolomics (methods)
• Middle Aged
• Pulmonary Disease, Chronic Obstructive (blood, diagnosis)
• Pulmonary Emphysema (blood, diagnosis)
• Real-Time Polymerase Chain Reaction