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

Dorothy M. Ryan, Thomas L. Vincent, Jacqueline Salit, Matthew S. Walters, Francisco Agosto-Perez, Renat Shaykhiev, Yael Strulovici-Barel, Robert J. Downey, Lauren J. Buro-Auriemma, Michelle R. Staudt, Neil R. Hackett, Jason G. Mezey, Ronald Crystal

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere88051
JournalPLoS One
Volume9
Issue number2
DOIs
Publication statusPublished - 3 Feb 2014
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Ryan, D. M., Vincent, T. L., Salit, J., Walters, M. S., Agosto-Perez, F., Shaykhiev, R., Strulovici-Barel, Y., Downey, R. J., Buro-Auriemma, L. J., Staudt, M. R., Hackett, N. R., Mezey, J. G., & Crystal, R. (2014). Smoking dysregulates the human airway basal cell transcriptome at COPD risk locus 19q13.2. PLoS One, 9(2), [e88051]. https://doi.org/10.1371/journal.pone.0088051