title: Nitric oxide synthase polymorphisms, gene expression and lung function in chronic obstructive pulmonary disease.
abstract: BACKGROUND
  Due to the pleiotropic effects of nitric oxide (NO) within the lungs, it is likely that NO is a significant factor in the pathogenesis of chronic obstructive pulmonary disease (COPD). The aim of this study was to test for association between single nucleotide polymorphisms (SNPs) in three NO synthase (NOS) genes and lung function, as well as to examine gene expression and protein levels in relation to the genetic variation.
  
  
  METHODS
  One SNP in each NOS gene (neuronal NOS (NOS1), inducible NOS (NOS2), and endothelial NOS (NOS3)) was genotyped in the Lung Health Study (LHS) and correlated with lung function. One SNP (rs1800779) was also analyzed for association with COPD and lung function in four COPD case-control populations. Lung tissue expression of NOS3 mRNA and protein was tested in individuals of known genotype for rs1800779. Immunohistochemistry of lung tissue was used to localize NOS3 expression.
  
  
  RESULTS
  For the NOS3 rs1800779 SNP, the baseline forced expiratory volume in one second in the LHS was significantly higher in the combined AG + GG genotypic groups compared with the AA genotypic group. Gene expression and protein levels in lung tissue were significantly lower in subjects with the AG + GG genotypes than in AA subjects. NOS3 protein was expressed in the airway epithelium and subjects with the AA genotype demonstrated higher NOS3 expression compared with AG and GG individuals. However, we were not able to replicate the associations with COPD or lung function in the other COPD study groups.
  
  
  CONCLUSIONS
  Variants in the NOS genes were not associated with lung function or COPD status. However, the G allele of rs1800779 resulted in a decrease of NOS3 gene expression and protein levels and this has implications for the numerous disease states that have been associated with this polymorphism.
authors.forename: Farzian
authors.initials: F
authors.lastname: Aminuddin
authors.forename: Tillie-Louise
authors.initials: TL
authors.lastname: Hackett
authors.forename: Dorota
authors.initials: D
authors.lastname: Stefanowicz
authors.forename: Aabida
authors.initials: A
authors.lastname: Saferali
authors.forename: Peter D
authors.initials: PD
authors.lastname: Paré
authors.forename: Amund
authors.initials: A
authors.lastname: Gulsvik
authors.forename: Per
authors.initials: P
authors.lastname: Bakke
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cho
authors.forename: Augusto
authors.initials: A
authors.lastname: Litonjua
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.forename: Wayne H
authors.initials: WH
authors.lastname: Anderson
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.affiliation: The University of British Columbia James Hogg Research Centre, Providence Heart + Lung Institute, Vancouver, Canada. andrew.sandford@hli.ubc.ca.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sandford
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D005541:Forced Expiratory Volume; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052248:Nitric Oxide Synthase Type I / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000737:chemistry / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000503:physiopathology*; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D012333:RNA, Messenger; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III