Nitric oxide synthase polymorphisms, gene expression and lung function in chronic obstructive pulmonary disease.

TitleNitric oxide synthase polymorphisms, gene expression and lung function in chronic obstructive pulmonary disease.
Publication TypeJournal Article
Year of Publication2013
AuthorsAminuddin, F, Hackett, T-L, Stefanowicz, D, Saferali, A, Paré, PD, Gulsvik, A, Bakke, P, Cho, MH, Litonjua, A, Lomas, DA, Anderson, WH, Beaty, TH, Silverman, EK, Sandford, AJ
JournalBMC Pulm Med
Volume13
Pagination64
Date Published2013
ISSN1471-2466
KeywordsAdult, Aged, Case-Control Studies, Female, Forced Expiratory Volume, Gene Expression, Genotype, Humans, Male, Middle Aged, Nitric Oxide Synthase, Nitric Oxide Synthase Type I, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive, RNA, Messenger
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.

DOI10.1186/1471-2466-13-64
Alternate JournalBMC Pulm Med
PubMed ID24192154
PubMed Central IDPMC3827989
Grant List5R01HL064068-04 / HL / NHLBI NIH HHS / United States
G0901786 / / Medical Research Council / United Kingdom
/ / Canadian Institutes of Health Research / Canada