Association of lung function decline with the heme oxygenase-1 gene promoter microsatellite polymorphism in a general population sample. Results from the European Community Respiratory Health Survey (ECRHS), France

Abstract

Inducible heme oxygenase (HO-1) acts against oxidants that are thought to play a major role in the pathogenesis of chronic obstructive pulmonary disease (COPD), characterised by impaired lung function. A (GT) n repeat polymorphism in the HO-1 gene promoter can modulate the gene transcription in response to oxidative stress. We hypothesised that this polymorphism could be associated with the level of lung function and decline in subjects exposed to oxidative agression (smokers). We genotyped 749 French subjects (20-44 years, 50% men, 40% never smokers) examined in both 1992 and 2000 as part of the ECRHS. Lung function was assessed by forced expiratory volume in 1 second (FEV 1 ) and FEV 1 /forced ventilatory capacity (FVC) ratio. We compared long (L) allele carriers ((GT) n >33 repeats for one or two alleles) to non-carriers. Cross sectionally, in 2000, L allele carriers showed lower FEV 1 / FVC than non-carriers. During the 8 year period, the mean annual FEV 1 and FEV 1 /FVC declines were 230.9 (31.1) ml/ year and 21.8 (6.1) U/year, respectively. FEV 1 /FVC decline was steeper in L allele carriers than in non-carriers (22.6 (5.5) v 21.5 (6.4), p = 0.07). There was a strong interaction between the L allele and smoking. In 2000, the L allele was associated with lower FEV 1 and FEV 1 /FVC in heavy smokers (>20 cigarettes/day) only (p for interaction = 0.07 and 0.002 respectively). Baseline heavy smokers carrying the L allele showed the steepest FEV 1 decline (262.0 (29.5 ml/year) and the steepest FEV 1 /FVC decline (28.8 (5.4 U/year) (p for interaction = 0.009 and 0.0006).These results suggest that a long (L) HO-1 gene promoter in heavy smokers is associated with susceptibility to develop airway obstruction.

Pharmacological and Clinical Aspects of Heme Oxygenase

“…Results from the European Community respiratory health survey in France showed that long HO-1 gene promoter (GT) n repeats in heavy smokers are associated with susceptibility to develop lung dysfunction and airway obstruction (Guénégou et al, 2006). Lung dysfunction as a result of lung cancer was seen in Japanese patients with long GT repeats of HO-1; however, this effect was limited to male patients (Kikuchi et al, 2005).…”

HMOX1andGSTvariants modify attenuation of FEF25–75%decline due to PM10reduction

“…For comparability with previous studies showing associations of o33 repeats with lung function [7,8], repeat genotypes were classified as having at least one long allele (o33 repeats) or not. The allele distribution in the study population is presented in figure 2.…”

“…a genetic variant consisting of a variable number of short nucleotide sequence repetitions (in this case ''GT''), is known in the promoter region of the HMOX1 gene. In general population samples from France and the Netherlands, long repeat alleles (o33 repeats) were associated with accelerated decline in several lung function parameters, especially among smokers [7,8].…”

NFE2L2 pathway polymorphisms and lung function decline in chronic obstructive pulmonary disease

“…SNPs in classical NFE2L2 targets such as glutathione S-transferase (GST) genes, NAD(P)H quinone oxidoreductase (NQO1), glutamate-cysteine ligase catalytic subunit (GCLC), and heme oxygenase-1 (HMOX1) have previously been shown to be associated with COPD (7,18,20,21,29,33,44,55,56,65,69). In contrast, other studies failed to find association of these genes with COPD-related phenotypes (23,24,57,67,68).…”