Aquaporin 5 Polymorphisms and Rate of Lung Function Decline in Chronic Obstructive Pulmonary Disease

Nadia N Hansel,John E Connett,Robert A Wise,Li Gao,Peisong Gao,Landon S King,Terri H Beaty,Renaldo Williams,Kathleen C Barnes,Rasika A Mathias,Venkataramana Sidhaye,Nicholas M Rafaels,Dominik Hartl

doi:10.1371/journal.pone.0014226

Nadia N Hansel, John E Connett + Show 11 more

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https://doi.org/10.1371/journal.pone.0014226

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Abstract

RationaleAquaporin-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).MethodsFive 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.ResultsAmong 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.ConclusionsPolymorphisms 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.

Highlights

chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and the fifth leading cause of death worldwide and its prevalence is expected to increase in coming decades.[1,2] The overwhelming majority of COPD is caused by environmental exposures
Aquaporins are water-specific membrane channel proteins and aquaporin 5 (AQP5) is found in airway epithelial cells, type I alveolar epithelial cells and submucosal gland acinar cells in the lungs where it plays a key role in water transport.[6]
Single-marker analyses All single nucleotide polymorphism (SNP) were in Hardy-Weinberg Equilibrium (HWE)

Summary

Introduction

COPD is the fourth leading cause of death in the United States and the fifth leading cause of death worldwide and its prevalence is expected to increase in coming decades.[1,2] The overwhelming majority of COPD is caused by environmental exposures. In the United States, this exposure is primarily cigarette smoke; only 15% of smokers develop COPD,[3] suggesting an important role for genetic susceptibility. Decreased expression of human AQP5 has been associated with mucus overproduction in the airways of subjects with COPD and lower lung function.[7] smoking has been shown to attenuate the expression of AQP5 in submucosal glands of subjects with COPD.[7] These data support a potential role of AQP5 in severity of airflow obstruction in COPD and suggest that the expression of AQP5 may be modified by smoking exposure

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