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

BMC Pulmonary Medicine

Andrew J Sandford²  Edwin K Silverman⁵  Terri H Beaty³  Wayne H Anderson¹  David A Lomas⁴  Augusto Litonjua⁵  Michael H Cho⁵  Per Bakke⁶  Amund Gulsvik⁶  Peter D Paré²  Aabida Saferali²  Dorota Stefanowicz²  Tillie-Louise Hackett²  Farzian Aminuddin² 

[1] GlaxoSmithKline Research and Development, Research Triangle Park, South of Durham, NC, USA;The University of British Columbia James Hogg Research Centre, Providence Heart + Lung Institute, Vancouver, Canada;Johns Hopkins School of Public Health, Baltimore, MD, USA;Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK;Channing Laboratory and Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA;Haukeland University Hospital and Institute of Medicine, University of Bergen, Bergen, Norway

关键词: Gene expression;    Polymorphism;    Nitric oxide synthase;    Chronic obstructive pulmonary disease;   

Others  :  1109631
DOI  :  10.1186/1471-2466-13-64

 received in 2013-07-31, accepted in 2013-10-31,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Aminuddin et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

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