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Title: Functional interactors of genomewide association study genes are differentially expressed in severe chronic obstructive pulmonary disease lung tissue      
Transcriptome or Gene expression
Multiple gene expression studies have been performed in lung or airway tissues from subjects with chronic obstructive pulmonary disease (COPD). However, in comparison to genome-wide association studies (GWAS), there has been poor replication across these studies. We sought to perform gene expression profiling on a large sample of severe COPD cases and control smokers and use network methods to identify interacting genes and pathways. We collected surgically-resected lung tissue samples from subjects with severe COPD and controls with normal lung function; all subjects were former smokers. Gene expression profiling on homogenized lung tissue was performed using Illumina HumanHT-12 BeadChips. Protein and RNA binding studies, RNA-interference, a murine smoking model, and expression quantitative trait locus analyses were used to identify genes and proteins that may interact with three known COPD GWAS genes: IREB2, HHIP and FAM13A. Weighted Gene Co-Expression Network Analysis (WGCNA) was used to define co-expressed gene modules. Comparing 111 COPD cases and 40 control smokers, 214 genes were differentially expressed; none of these genes were at significant GWAS loci. However, the top differentially expressed gene was HMGB1, which interacts with AGER, a gene implicated through COPD GWAS. The genes differentially expressed in lung tissue showed strong enrichment for putative interactors of IREB2 and HHIP, with less support for FAM13A, based on the gene sets from the in vitro, in vivo, and in silico studies. In the WGCNA, the module most highly associated for COPD was enriched for B-cell pathways, which shared seventeen genes with the results of the Hhip+/- mouse smoking model. As in other common diseases, genes at COPD GWAS loci were not differentially expressed with COPD status; however, using a combination of network methods, experimental studies of interaction and careful phenotype definition, we found differential expression of putative interactors of these genes, and we replicated previous human and mouse microarray results involving B cell pathways. Overall design: Lung tissue samples were snap frozen and stored at -80oC. RNA and DNA were simultaneously extracted from the homogenized lung tissue using the AllPrep kit (Qiagen, Valenica, CA). RNA quality was assessed on a BioAnalyzer (Agilent, Santa Clara, CA). Gene expression profiling was performed using HumanHT-12 BeadChips (Illumina, San Diego, CA).
Homo sapiens
National Center for Biotechnology Information
NCBI BioProject
  • R01 HL113264/HL/NHLBI NIH HHS/United States

  • R01 HL089897/HL/NHLBI NIH HHS/United States

  • N01HR76106/HL/NHLBI NIH HHS/United States

  • N01HR76101/HL/NHLBI NIH HHS/United States

  • N01HR76112/HL/NHLBI NIH HHS/United States

  • R00 HL125899/HL/NHLBI NIH HHS/United States

  • R25 ES011080/ES/NIEHS NIH HHS/United States

  • N01HR76108/HL/NHLBI NIH HHS/United States

  • N01HR76109/HL/NHLBI NIH HHS/United States

  • R01 HL130512/HL/NHLBI NIH HHS/United States

  • R01 HL094635/HL/NHLBI NIH HHS/United States

  • N01HR76103/HL/NHLBI NIH HHS/United States

  • N01HR76113/HL/NHLBI NIH HHS/United States

  • N01HR76102/HL/NHLBI NIH HHS/United States

  • N01HR76107/HL/NHLBI NIH HHS/United States

  • R01 HL089856/HL/NHLBI NIH HHS/United States

  • N01HR76114/HL/NHLBI NIH HHS/United States

  • N01HR76110/HL/NHLBI NIH HHS/United States

  • R33 HL120794/HL/NHLBI NIH HHS/United States

  • P01 HL105339/HL/NHLBI NIH HHS/United States

  • N01HR76119/HL/NHLBI NIH HHS/United States

  • N01HR76105/HL/NHLBI NIH HHS/United States

  • N01 HR076115/HR/NHLBI NIH HHS/United States

  • N01HR76111/HL/NHLBI NIH HHS/United States

  • R01 HL125583/HL/NHLBI NIH HHS/United States

  • N01HR76116/HL/NHLBI NIH HHS/United States

  • R01 HL127200/HL/NHLBI NIH HHS/United States

  • N01HR76118/HL/NHLBI NIH HHS/United States

  • R01 HL111759/HL/NHLBI NIH HHS/United States

  • N01HR76104/HL/NHLBI NIH HHS/United States


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