Functional interactors of three genome-wide association study genes are differentially expressed in severe chronic obstructive pulmonary disease lung tissue

• Published in: Scientific reports Vol. 7; no. 1; p. 44232
• Main Authors: Morrow, Jarrett D., Zhou, Xiaobo, Lao, Taotao, Jiang, Zhiqiang, DeMeo, Dawn L., Cho, Michael H., Qiu, Weiliang, Cloonan, Suzanne, Pinto-Plata, Victor, Celli, Bartholome, Marchetti, Nathaniel, Criner, Gerard J., Bueno, Raphael, Washko, George R., Glass, Kimberly, Quackenbush, John, Choi, Augustine M. K., Silverman, Edwin K., Hersh, Craig P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.03.2017; Nature Publishing Group
• Subjects: 38/39; 45/61; 631/208/191/2018; 631/208/199; 692/699/1785/4037; Adult; Aged; Animals; Chronic obstructive pulmonary disease; DNA microarrays; Emphysema; Female; Gene expression; Gene Expression Regulation; Gene mapping; Genetic Loci; Genome-wide association studies; Genome-Wide Association Study; Genomes; HMGB1 protein; Humanities and Social Sciences; Humans; Lung - metabolism; Lung - pathology; Lung diseases; Lymphocytes B; Male; Mice; Middle Aged; multidisciplinary; Obstructive lung disease; Pulmonary Disease, Chronic Obstructive - genetics; Pulmonary Disease, Chronic Obstructive - metabolism; Pulmonary Disease, Chronic Obstructive - pathology; Quantitative trait loci; Ribonucleic acid; RNA; RNA-mediated interference; Science; Severity of Illness Index; Smoking; Studies
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep44232

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.