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

We 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.We 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.We 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.Oxidative stress induced by smoking is considered to play a role in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Oxidant compounds in cigarette smoke cause an excess of oxidants in the lung, and lead to direct cell injury, lung extracellular matrix damage, inactivation of antiproteinases, and induction of proinflammatory mediators [1].Heme oxygenase-1 (HMOX1) is an essential enzyme in heme catabolism and is induced by oxidative stress. HMOX1 catalyzes the conversion of heme to biliverdin, carbon monoxide and iron. Subsequent to the reaction, biliverdin is converted to bilirubin by biliverdin reductase. Biliverdin and bilirubin