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Smoking-Related Small Airway Epithelium Dysregulated Genes that Are Shared by Most Smokers
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A3577 - Smoking-Related Small Airway Epithelium Dysregulated Genes that Are Shared by Most Smokers
Author Block: Y. Strulovici-Barel1, J. Salit1, S. L. O'Beirne1, H. Bitter2, H. Hilton2, G. Wolff2, C. Stevenson2, S. Visvanathan2, J. S. Fine2, R. G. Crystal1; 1Weill Cornell Medical College, New York, NY, United States, 2Hoffmann-LaRoche, Nutley, NJ, United States.
Rationale: The small airway epithelium (SAE, >6th generations), the initiation site of most airway disorders, is highly sensitive to the stress of smoking, with marked dysregulation of its transcriptome. Based on the knowledge that SAE biology varies among smokers, and that smokers vary markedly in smoking habits (pack-yr history, age of smoking initiation) and extent (packs/day), we asked: despite these variabilities, are there SAE dysregulated genes shared by most smokers?
Methods: The SAE transcriptome was assessed in 4 cohorts: (1) 1° cohort - 23 nonsmokers (NS) and 37 healthy smokers (S) assessed at 4 time points over 1 yr (0, 3, 6, 12 months); (2) replication cohort (RC) 1 - 60 NS, 74 S; (3) RC2 - 6 NS, 10S; and (4) RC3 - 20 NS, 23 S. Smoking status was confirmed using urine cotinine levels. SAE was obtained by bronchoscopic brushings and processed on Affymetrix HG-U133 Plus 2.0 microarrays (1°, RC1,2) or Illumina HiSeq 2500 (RC3). For the 1° cohort, average SAE gene expression levels from all time points were calculated for each gene for each subject; an SAE smoking-related gene signature was calculated based on all differentially expressed genes in S vs NS; smoking-related genes with average expression level outside the normal range of NS ± 2 SD were defined as dysregulated. The smoking-related gene list dysregulated in most (≥75%) S in the 1° cohort was confirmed using RC1-3.
Results: Based on the average gene expression in the 1°cohort, 485 genes were differentially expressed in S vs NS [246 (51%) up-regulated, 239 (49%) down-regulated], of which 81 (17%) were dysregulated in ≥75% of S. Sixty-five (80%), 75 (93%) and 72 (89%) of the 81 genes were confirmed to be differentially expressed in S vs NS in RC1, RC2 and RC3, respectively. Fifty-five of the 81 genes (68%) were universally differentially expressed in all datasets in S vs NS [53 (96%) up-regulated, 2 (4%) down-regulated]. The top universal smoking-related genes were CYP1B1, AKR1B10, UCHL1, SPP1 and SFRP2 and the top functional categories oxidant-related (30%), metabolism (18%), transcription (9%), and signal transduction (9%). The top pathways enriched with these genes were pentose phosphate pathway, methylglyoxal degradation, and retinoate biosynthesis pathways.
Conclusions: Despite variability in smoking habits and the SAE response among smokers, there are commonly dysregulated SAE smoking-related genes shared by most smokers, providing targets for development of therapies that could be applicable in most individuals with smoking-related airway disease.
Author Block: Y. Strulovici-Barel1, J. Salit1, S. L. O'Beirne1, H. Bitter2, H. Hilton2, G. Wolff2, C. Stevenson2, S. Visvanathan2, J. S. Fine2, R. G. Crystal1; 1Weill Cornell Medical College, New York, NY, United States, 2Hoffmann-LaRoche, Nutley, NJ, United States.
Rationale: The small airway epithelium (SAE, >6th generations), the initiation site of most airway disorders, is highly sensitive to the stress of smoking, with marked dysregulation of its transcriptome. Based on the knowledge that SAE biology varies among smokers, and that smokers vary markedly in smoking habits (pack-yr history, age of smoking initiation) and extent (packs/day), we asked: despite these variabilities, are there SAE dysregulated genes shared by most smokers?
Methods: The SAE transcriptome was assessed in 4 cohorts: (1) 1° cohort - 23 nonsmokers (NS) and 37 healthy smokers (S) assessed at 4 time points over 1 yr (0, 3, 6, 12 months); (2) replication cohort (RC) 1 - 60 NS, 74 S; (3) RC2 - 6 NS, 10S; and (4) RC3 - 20 NS, 23 S. Smoking status was confirmed using urine cotinine levels. SAE was obtained by bronchoscopic brushings and processed on Affymetrix HG-U133 Plus 2.0 microarrays (1°, RC1,2) or Illumina HiSeq 2500 (RC3). For the 1° cohort, average SAE gene expression levels from all time points were calculated for each gene for each subject; an SAE smoking-related gene signature was calculated based on all differentially expressed genes in S vs NS; smoking-related genes with average expression level outside the normal range of NS ± 2 SD were defined as dysregulated. The smoking-related gene list dysregulated in most (≥75%) S in the 1° cohort was confirmed using RC1-3.
Results: Based on the average gene expression in the 1°cohort, 485 genes were differentially expressed in S vs NS [246 (51%) up-regulated, 239 (49%) down-regulated], of which 81 (17%) were dysregulated in ≥75% of S. Sixty-five (80%), 75 (93%) and 72 (89%) of the 81 genes were confirmed to be differentially expressed in S vs NS in RC1, RC2 and RC3, respectively. Fifty-five of the 81 genes (68%) were universally differentially expressed in all datasets in S vs NS [53 (96%) up-regulated, 2 (4%) down-regulated]. The top universal smoking-related genes were CYP1B1, AKR1B10, UCHL1, SPP1 and SFRP2 and the top functional categories oxidant-related (30%), metabolism (18%), transcription (9%), and signal transduction (9%). The top pathways enriched with these genes were pentose phosphate pathway, methylglyoxal degradation, and retinoate biosynthesis pathways.
Conclusions: Despite variability in smoking habits and the SAE response among smokers, there are commonly dysregulated SAE smoking-related genes shared by most smokers, providing targets for development of therapies that could be applicable in most individuals with smoking-related airway disease.
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