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- Title
Aquaporin 5 Polymorphisms and Rate of Lung Function Decline in Chronic Obstructive Pulmonary Disease.
- Authors
Hansel, Nadia N.; Sidhaye, Venkataramana; Rafaels, Nicholas M.; Gao, Li; Gao1, Peisong; Williams, Renaldo; Connett, John E.; Beaty, Terri H.; Mathias, Rasika A.; Wise, Robert A.; King, Landon S.; Barnes, Kathleen C.
- Abstract
Rationale: Aquaporin-5 (AQP5) can cause mucus overproduction and lower lung function. Genetic variants in the AQP5 gene might be associated with rate of lung function decline in chronic obstructive pulmonary disease (COPD). Methods: Five single nucleotide polymorphisms (SNPs) in AQP5 were genotyped in 429 European American individuals with COPD randomly selected from the NHLBI Lung Health Study. Mean annual decline in FEV1 % predicted, assessed over five years, was calculated as a linear regression slope, adjusting for potential covariates and stratified by smoking status. Constructs containing the wildtype allele and risk allele of the coding SNP N228K were generated using site-directed mutagenesis, and transfected into HBE-16 (human bronchial epithelial cell line). AQP5 abundance and localization were assessed by immunoblots and confocal immunofluoresence under control, shear stress and cigarette smoke extract (CSE 10%) exposed conditions to test for differential expression or localization. Results: Among continuous smokers, three of the five SNPs tested showed significant associations (0.02>P>0.004) with rate of lung function decline; no associations were observed among the group of intermittent or former smokers. Haplotype tests revealed multiple association signals (0.012>P>0.0008) consistent with the single-SNP results. In HBE16 cells, shear stress and CSE led to a decrease in AQP5 abundance in the wild-type, but not in the N228K AQP5 plasmid. Conclusions: Polymorphisms in AQP5 were associated with rate of lung function decline in continuous smokers with COPD. A missense mutation modulates AQP-5 expression in response to cigarette smoke extract and shear stress. These results suggest that AQP5 may be an important candidate gene for COPD.
- Subjects
AQUAPORINS; OBSTRUCTIVE lung diseases; CIGARETTE smoke; EPITHELIAL cells; GENETIC polymorphisms; EUROPEAN Americans; REGRESSION analysis; GENES; GENETICS
- Publication
PLoS ONE, 2010, Vol 5, Issue 12, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0014226