Effect of heme oxygenase-1 polymorphisms on lung function and gene expression

Goh Tanaka,Raja T Abboud,John E Connett,Farzian Aminuddin,Nicholas R Anthonisen,Peter D Paré,Andrew J Sandford,Jian-Qing He,Loubna Akhabir,Karey Shumansky

doi:10.1186/1471-2350-12-117

Abstract

BackgroundOxidative stress induced by smoking is considered to be important in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Heme oxygenase-1 (HMOX1) is an essential enzyme in heme catabolism that is induced by oxidative stress and may play a protective role as an antioxidant in the lung. We determined whether HMOX1 polymorphisms were associated with lung function in COPD patients and whether the variants had functional effects.MethodsWe genotyped five single nucleotide polymorphisms (SNPs) in the HMOX1 gene in Caucasians who had the fastest (n = 278) and the slowest (n = 304) decline of FEV1 % predicted, selected from smokers in the NHLBI Lung Health Study. These SNPs were also studied in Caucasians with the lowest (n = 535) or the highest (n = 533) baseline lung function. Reporter genes were constructed containing three HMOX1 promoter polymorphisms and the effect of these polymorphisms on H2O2 and hemin-stimulated gene expression was determined. The effect of the HMOX1 rs2071749 SNP on gene expression in alveolar macrophages was investigated.ResultsWe found a nominal association (p = 0.015) between one intronic HMOX1 SNP (rs2071749) and lung function decline but this did not survive correction for multiple comparisons. This SNP was in perfect linkage disequilibrium with rs3761439, located in the promoter of HMOX1. We tested rs3761439 and two other putatively functional polymorphisms (rs2071746 and the (GT)n polymorphism) in reporter gene assays but no significant effects on gene expression were found. There was also no effect of rs2071749 on HMOX1 gene expression in alveolar macrophages.ConclusionsWe found no association of the five HMOX1 tag SNPs with lung function decline and no evidence that the three promoter polymorphisms affected the regulation of the HMOX1 gene.

Highlights

Oxidative stress induced by smoking is considered to be important in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD)
Single single nucleotide polymorphism (SNP) analysis in the Lung Health Study (LHS) We analyzed each of the selected SNPs in the rate of lung function decline sub-study and the baseline lung function sub-study (Table 2)
The rs2071749 SNP was not associated with rate of decline of lung function expressed as a continuous variable in the fast decline group (p = 0.41)

Summary

Introduction

Oxidative stress induced by smoking is considered to be important in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Oxidative stress induced by smoking is considered to play a role in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Biliverdin and bilirubin have been shown to act as scavengers of reactive oxygen species, and carbon monoxide has been shown to possess anti-inflammatory effects (reviewed in [2]). In both in vitro and in vivo studies, murine cells lacking Hmox have been reported to be susceptible to oxidative injury [3], and exogenous delivery of Hmox by gene transfer in the rat lung was shown to provide protection against hyperoxia-induced injury [4]. The results of these studies suggest that HMOX1 has a protective role as an antioxidant in the lung

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Discussion

Conclusion