Genomic copy number determines functional expression of {beta}-defensin 2 in airway epithelial cells and associates with chronic obstructive pulmonary disease.
BACKGROUND
Copy number variations of the cluster of beta-defensin genes have been associated with psoriasis and inflammatory bowel disease. Controversy still exists on whether the beta-defensins genes determine susceptibility for chronic obstructive pulmonary disease (COPD).


OBJECTIVE
We investigated whether genomic copy number variations of the beta-defensin gene cluster have a functional role in airway epithelial cells and associate with the presence of COPD.


METHODS
Baseline and inflammatory induced transcript expression of DEFB4 was studied in nasal epithelial cell cultures and its effect on Pseudomonas aeruginosa inhibition was assessed. Subsequently, relevant functional cut-offs for copy numbers were used to explore associations with COPD in two independent case-control studies.


RESULTS
Copy number variation in the beta-defensin encoding genes correlated with baseline mRNA DEFB4 expression levels (R(2) = 0.96; P = 0.02), with a plateau effect from five copies or more. Only when higher copy numbers of beta-defensin genes were present, transcription was significantly up-regulated by tumor necrosis factor-alpha (P < 0.0001), which resulted in better antimicrobial activity in vitro. When comparing healthy smokers with COPD patients, a copy number greater than or equal to 5 was associated with increased risk for COPD with an adjusted odds ratio of 1.8 (confidence interval, 1.1-2.8; P = 0.02), which was confirmed by a second independent case-control study.


CONCLUSIONS
Genomic copy number variation of beta-defensin encoding genes has a functional role in airway epithelial cells, which may contribute to the pathogenesis of COPD.
Janssens
Wim
W
Department of Human Genetics, Katholieke Universiteit Leuven, Gasthuisberg O&N1 (602), Herestraat 49, B-3000, Leuven, Belgium.
Nuytten
Hilde
H
Dupont
Lieven J
LJ
Van Eldere
Johan
J
Vermeire
Severine
S
Lambrechts
Diether
D
Nackaerts
Kristiaan
K
Decramer
Marc
M
Cassiman
Jean-Jacques
JJ
Cuppens
Harry
H
D000368:Aged; D016022:Case-Control Studies; D002478:Cells, Cultured; D004171:Diploidy; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009297:Nasal Mucosa / Q000166:cytology; D016133:Polymerase Chain Reaction; D011550:Pseudomonas aeruginosa; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation; D023083:beta-Defensins / Q000235:genetics*
C106641:DEFB4A protein, human; D016209:Interleukin-8; D012333:RNA, Messenger; D023083:beta-Defensins