title: Aquaporin 5 polymorphisms and rate of lung function decline in chronic obstructive pulmonary disease.
abstract: BACKGROUND
  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 FEV(1) % 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 immunofluorescence 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.
authors.affiliation: Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Nadia N
authors.initials: NN
authors.lastname: Hansel
authors.forename: Venkataramana
authors.initials: V
authors.lastname: Sidhaye
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Rafaels
authors.forename: Li
authors.initials: L
authors.lastname: Gao
authors.forename: Peisong
authors.initials: P
authors.lastname: Gao
authors.forename: Renaldo
authors.initials: R
authors.lastname: Williams
authors.forename: John E
authors.initials: JE
authors.lastname: Connett
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
authors.forename: Rasika A
authors.initials: RA
authors.lastname: Mathias
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wise
authors.forename: Landon S
authors.initials: LS
authors.lastname: King
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Barnes
mesh_terms: D051402:Aquaporin 5 / Q000235:genetics*; D002460:Cell Line; D005787:Gene Frequency; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D008168:Lung / Q000502:physiology*; D015233:Models, Statistical; D010957:Plasmids / Q000378:metabolism; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*; D012129:Respiratory Function Tests; D012907:Smoking
chemical_list: D051402:Aquaporin 5