title: Effect of heme oxygenase-1 polymorphisms on lung function and gene expression.
abstract: BACKGROUND
  Oxidative 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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: UBC James Hogg Research Center, Providence Heart + Lung Institute, St, Paul's Hospital, Vancouver, B.C., Canada.
authors: Goh
authors: G
authors: Tanaka
authors: Farzian
authors: F
authors: Aminuddin
authors: Loubna
authors: L
authors: Akhabir
authors: Jian-Qing
authors: JQ
authors: He
authors: Karey
authors: K
authors: Shumansky
authors: John E
authors: JE
authors: Connett
authors: Nicholas R
authors: NR
authors: Anthonisen
authors: Raja T
authors: RT
authors: Abboud
authors: Peter D
authors: PD
authors: Paré
authors: Andrew J
authors: AJ
authors: Sandford
mesh_terms: D000328:Adult; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005541:Forced Expiratory Volume / Q000235:genetics / Q000502:physiology; D015870:Gene Expression; D055106:Genome-Wide Association Study; D006239:Haplotypes; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000503:physiopathology*; D016676:Macrophages, Alveolar / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology*
chemical_list: D017931:DNA Primers; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1