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

Overview

MeSH

  • Adult
  • DNA Copy Number Variations
  • DNA Methylation
  • Genome-Wide Association Study
  • Humans
  • Oligonucleotide Array Sequence Analysis

MeSH Major

  • Biomarkers
  • Chromosomes, Human, Pair 19
  • Endothelial Cells
  • Gene Expression Profiling
  • Genetic Loci
  • Pulmonary Disease, Chronic Obstructive
  • Respiratory Mucosa
  • Smoking

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.

publication date

  • 2014

has subject area

  • Adult
  • 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

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3912203

Digital Object Identifier (DOI)

  • 10.1371/journal.pone.0088051

PubMed ID

  • 24498427

Additional Document Info

start page

  • e88051

volume

  • 9

number

  • 2