Smoking dysregulates the human airway basal cell transcriptome at COPD risk locus 19q13.2.

Publication TypeJournal Article
Year of Publication2014
AuthorsRyan DM, Vincent TL, Salit J, Walters MS, Agosto-Perez F, Shaykhiev R, Strulovici-Barel Y, Downey RJ, Buro-Auriemma LJ, Staudt MR, Hackett NR, Mezey JG, Crystal RG
JournalPLoS One
Date Published2014
KeywordsAdult, Biomarkers, Chromosomes, Human, Pair 19, DNA Copy Number Variations, DNA Methylation, Endothelial Cells, Gene Expression Profiling, Genetic Loci, Genome-Wide Association Study, Humans, Oligonucleotide Array Sequence Analysis, Pulmonary Disease, Chronic Obstructive, Respiratory Mucosa, Smoking

Genome-wide association studies (GWAS) and candidate gene studies have identified a number of risk loci associated with the smoking-related disease COPD, a disorder that originates in the airway epithelium. Since airway basal cell (BC) stem/progenitor cells exhibit the earliest abnormalities associated with smoking (hyperplasia, squamous metaplasia), we hypothesized that smoker BC have a dysregulated transcriptome, enriched, in part, at known GWAS/candidate gene loci. Massive parallel RNA sequencing was used to compare the transcriptome of BC purified from the airway epithelium of healthy nonsmokers (n = 10) and healthy smokers (n = 7). The chromosomal location of the differentially expressed genes was compared to loci identified by GWAS to confer risk for COPD. Smoker BC have 676 genes differentially expressed compared to nonsmoker BC, dominated by smoking up-regulation. Strikingly, 166 (25%) of these genes are located on chromosome 19, with 13 localized to 19q13.2 (p<10⁻⁴ compared to chance), including 4 genes (NFKBIB, LTBP4, EGLN2 and TGFB1) associated with risk for COPD. These observations provide the first direct connection between known genetic risks for smoking-related lung disease and airway BC, the population of lung cells that undergo the earliest changes associated with smoking.

Alternate JournalPLoS ONE
PubMed ID24498427
PubMed Central IDPMC3912203
Grant ListT32HL094284 / HL / NHLBI NIH HHS / United States
UL1RR024143 / RR / NCRR NIH HHS / United States
P50HL51746 / HL / NHLBI NIH HHS / United States
UL1TR000457 / TR / NCATS NIH HHS / United States
R01HL107882 / HL / NHLBI NIH HHS / United States