title: COPD subtypes identified by network-based clustering of blood gene expression.
abstract: One of the most common smoking-related diseases, chronic obstructive pulmonary disease (COPD), results from a dysregulated, multi-tissue inflammatory response to cigarette smoke. We hypothesized that systemic inflammatory signals in genome-wide blood gene expression can identify clinically important COPD-related disease subtypes, and we leveraged pre-existing gene interaction networks to guide unsupervised clustering of blood microarray expression data. Using network-informed non-negative matrix factorization, we analyzed genome-wide blood gene expression from 229 former smokers in the ECLIPSE Study, and we identified novel, clinically relevant molecular subtypes of COPD. These network-informed clusters were more stable and more strongly associated with measures of lung structure and function than clusters derived from a network-naïve approach, and they were associated with subtype-specific enrichment for inflammatory and protein catabolic pathways. These clusters were successfully reproduced in an independent sample of 135 smokers from the COPDGene Study.
authors.affiliation: Department of Computer Science, Northeastern University, Boston, USA.
authors.forename: Yale
authors.initials: Y
authors.lastname: Chang
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Glass
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, USA.
authors.forename: Yang-Yu
authors.initials: YY
authors.lastname: Liu
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, USA; Pulmonary and Critical Care Division, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.affiliation: Department of Medicine, National Jewish Health, Denver, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.affiliation: GSK R&D, King of Prussia, PA, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Tal-Singer
authors.affiliation: Department of Medicine, National Jewish Health, Denver, USA.
authors.forename: Russ
authors.initials: R
authors.lastname: Bowler
authors.affiliation: Department of Computer Science, Northeastern University, Boston, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dy
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, USA; Pulmonary and Critical Care Division, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Cho
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, USA; Division of General Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA. Electronic address: peter.castaldi@channing.harvard.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Castaldi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods*; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000235:genetics*; D012907:Smoking / Q000097:blood / Q000235:genetics*
keywords: Chronic obstructive pulmonary disease; Disease subtypes; Gene expression; Network analysis; Smoking