title: Functional interactors of three genome-wide association study genes are differentially expressed in severe chronic obstructive pulmonary disease lung tissue.
abstract: In comparison to genome-wide association studies (GWAS), there has been poor replication of gene expression studies in chronic obstructive pulmonary disease (COPD). We performed microarray gene expression profiling on a large sample of resected lung tissues from subjects with severe COPD. Comparing 111 COPD cases and 40 control smokers, 204 genes were differentially expressed; none were at significant GWAS loci. The top differentially expressed gene was HMGB1, which interacts with AGER, a known COPD GWAS gene. Differentially expressed genes showed enrichment for putative interactors of the first three identified COPD GWAS genes IREB2, HHIP, and FAM13A, based on gene sets derived from protein and RNA binding studies, RNA-interference, a murine smoking model, and expression quantitative trait locus analyses. The gene module most highly associated for COPD in Weighted Gene Co-Expression Network Analysis (WGCNA) was enriched for B cell pathways, and shared seventeen genes with a mouse smoking model and twenty genes with previous emphysema studies. As in other common diseases, genes at COPD GWAS loci were not differentially expressed; however, using a combination of network methods, experimental studies and careful phenotype definition, we found differential expression of putative interactors of these genes, and we replicated previous human and mouse microarray results.
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Jarrett D
authors.initials: JD
authors.lastname: Morrow
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Taotao
authors.initials: T
authors.lastname: Lao
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.|Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Dawn L
authors.initials: DL
authors.lastname: DeMeo
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.|Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cho
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Qiu
authors.affiliation: Department of Medicine, New York Presbyterian/Weill Cornell Medical Center, New York, NY, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Cloonan
authors.affiliation: Department of Critical Care Medicine and Pulmonary Disease, Baystate Medical Center, Springfield, MA, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Pinto-Plata
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Bartholome
authors.initials: B
authors.lastname: Celli
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Temple University, Philadelphia, PA, USA.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Marchetti
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Temple University, Philadelphia, PA, USA.
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Criner
authors.affiliation: Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Bueno
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: George R
authors.initials: GR
authors.lastname: Washko
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Glass
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Quackenbush
authors.affiliation: Department of Medicine, New York Presbyterian/Weill Cornell Medical Center, New York, NY, USA.
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.|Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.|Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Craig P
authors.initials: CP
authors.lastname: Hersh
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012720:Severity of Illness Index