Smoking dysregulates the human airway basal cell transcriptome at COPD risk locus 19q13.2.
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.
Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
Dorothy M
DM
Ryan
Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
Thomas L
TL
Vincent
Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
Jacqueline
J
Salit
Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
Matthew S
MS
Walters
Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America.
Francisco
F
Agosto-Perez
Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
Renat
R
Shaykhiev
Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
Yael
Y
Strulovici-Barel
Thoracic Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
Robert J
RJ
Downey
Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
Lauren J
LJ
Buro-Auriemma
Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
Michelle R
MR
Staudt
Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
Neil R
NR
Hackett
Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America ; Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America.
Jason G
JG
Mezey
Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
Ronald G
RG
Crystal
D000328:Adult; D015415:Biomarkers / Q000378:metabolism*; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D019175:DNA Methylation; D042783:Endothelial Cells / Q000378:metabolism*; D020869:Gene Expression Profiling; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D029424:Pulmonary Disease, Chronic Obstructive / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012907:Smoking / Q000009:adverse effects* / Q000235:genetics
D015415:Biomarkers