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Oxidative stress is thought to play a major role in the pathogenesis of chronic obstructive pulmonary disease, characterized by impaired lung function. A large number (> or =33) of GT repeats (L-allele) in the gene of the powerful antioxidant enzyme heme oxygenase-1 has been associated with susceptibility to accelerated lung function decline. In contrast, beta-carotene may help to protect against accelerated decline. To determine whether high serum levels of beta-carotene might counterbalance the greater susceptibility of L-allele carriers, the authors analyzed the annual decline in forced expiratory volume in 1 second (FEV1) in a general population sample of 523 French subjects (20-44 years, 50% men) examined in 1992 and 2000 as part of the European Community Respiratory Health Survey. Analysis of covariance, adjusted for sex as well as baseline age, body mass index, smoking, and FEV1, showed that, among subjects with low beta-carotene levels, L-allele carriers experienced a steeper mean FEV1 decline than did noncarriers (mean = -58.8, 95% confidence interval: -73.2, -44.5 vs. mean = -34.7, 95% confidence interval: -38.9, -29.8 ml/year) (p = 0.009), whereas among subjects with high beta-carotene levels, the FEV1 decline was not different in L-allele carriers and noncarriers (two-sided p = 0.9). The results suggest that high levels of beta-carotene might counterbalance the effects on FEV1 decline of a genetically determined deficiency in antioxidant response.

Background A higher exposure to bacterial compounds is purported to explain the lower prevalence of allergy in farm children, but responsiveness to bacterial compounds is modulated by genetic factors. Objective To assess whether the protective effect of farm exposure on atopy is influenced by a CD14 promoter functional polymorphism. Methods We administered a detailed questionnaire on farm exposure in childhood and genotyped the CD14 C-159T polymorphism in 2 French centers participating in the European Community Respiratory Health Survey (ECRHS)–II. Results Six hundred randomly selected young adults provided blood samples for IgE measurements and had CD14 C-159T genotyped. Exposure to a farming environment in early life was associated with a reduced risk of nasal allergies (odds ratio [OR], 0.54; 95% CI, 0.29-1.00) and atopic sensitization (OR, 0.47; 95% CI, 0.24-0.93) in adulthood. A lower risk of allergic rhinitis and atopy was also observed in carriers of the CD14-159TT genotype compared with −159CC subjects (OR, 0.52; 95% CI, 0.30-0.88; and OR, 0.54; 95% CI, 0.31-0.92, respectively). When farm exposure and CD14 C-159T were considered together, the risk of nasal allergies and atopy was the most reduced in the subjects who combined both an early-life exposure to a farming environment and the −159TT genotype (OR, 0.26; 95% CI, 0.07-0.94; and OR, 0.21; 95% CI, 0.05-0.93, respectively, vs nonexposed −159CC+CT subjects). The results were consistent in the 2 centers, supporting the validity of the results. Conclusion A gene-by-environment interaction between CD14 C-159T and environmental exposure in childhood may modify the development of atopy. Clinical implications This polymorphism should be considered in interventions studies that use microbial stimuli to reduce sensitization.

RESUME Les oxydants pourraient etre impliques dans la Physiopathologie de la BPCO (Broncho-Pneumopathie Chronique Obstructive), definie par une diminution des debits aeriens progressive et incompletement reversible. L’HO-1 (heme oxygenase-1 ) est un antioxydant puissant. Il a ete montre qu’un polymorphisme microsatellite du promoteur du gene de l’HO-1 (repetition de paires de bases (GT)) etait capable de moduler la transcription du gene en reponse au stress oxydant. Un promoteur long serait associe a une expression de la proteine HO-1 moindre. Nous avons emis l’hypothese que ce polymorphisme pourrait etre associe au declin de la fonction pulmonaire chez des sujets exposes a une agression oxydante importante comme les fumeurs. Pour tester cette hypothese, nous avons genotype 749 sujets (âges de 20 a 44 ans, 50 % d’hommes et 40 % de non-fumeurs) examines en 1992 et en 2000 dans le cadre du recueil des donnees francaises de l’etude ECRHS. Nous avons compare les porteurs d’allele long (L) ((GT)n ≥ 33 repetitions sur un ou deux allele (s)) aux autres. En longitudinal, nous avons observe que le declin de la fonction pulmonaire etait accelere chez les porteurs de l’allele L par rapport aux autres. En outre, il y avait une interaction entre l’allele L et le tabagisme : le declin de la fonction pulmonaire etait accelere dans le groupe des gros fumeurs porteurs de l’allele L par rapport aux gros fumeurs non-porteurs de l’allele L et aux porteurs de l’allele L non-gros fumeurs. Nos resultats suggerent donc qu’un promoteur long du gene de l’HO-1 serait associe, chez les gros fumeurs, au developpement d’un trouble ventilatoire obstructif.

Background Although asthma and rhinitis often occur together, the reason for this common comorbidity is still a matter of debate. Objective We sought to assess whether the coexistence of asthma and rhinitis could be explained by common risk factors. Methods International cross-sectional study of representative samples of young adults, who completed a detailed questionnaire and underwent lung function tests, bronchoprovocation challenge, IgE measurements, and skin prick tests. Results In all countries, asthma and bronchial hyperreactivity were more frequent in subjects with rhinitis than in those without (odds ratio [OR], 6.63; 95% CI, 5.44-8.08; and OR, 3.02 95% CI, 2.66-3.43, respectively). Seventy-four percent to 81% of subjects with asthma reported rhinitis, depending on sensitization to specific allergens. Conversely, the risk of asthma increased from 2.0% in subjects without rhinitis to 6.7% in subjects with rhinitis only when exposed to pollen, 11.9% in subjects with rhinitis when exposed to animals, and 18.8% in subjects with rhinitis either when exposed to pollen or to animals. The association between rhinitis and asthma remained significant after adjustment for total IgE, parental history of asthma, and allergen sensitization (OR, 3.41; 95% CI, 2.75-4.2 suggesting that the coexistence of asthma and rhinitis is not solely due to atopic predisposition to these 2 diseases. Conclusions Although there were some variations in the association between asthma and rhinitis according to sensitization to individual allergens, the strong association between asthma and rhinitis was not fully explained by shared risk factors, including atopy. Our findings are consistent with the hypothesis that rhinitis might increase the risk of asthma.

We investigated the role of heme oxygenase-1 (HO-1), a powerful anti-inflammatory and anti-oxidant enzyme, in modulating cigarette smoke (CS)-induced mucus secretion. In both rats and mice, 5-day CS exposure increased HO-1 expression and activity, mucus secretion, MUCIN 5AC (MUC5AC) gene and protein expression, and local inflammation, along with up-regulation of dual oxidase 1 gene expression and both the activity and phosphorylation of the epidermal growth factor receptor, which is involved in MUC5AC induction. Pharmacological induction of HO-1 prevented these actions and inhibition of HO-1 expression by a specific siRNA potentiated them. In French participants to the European Community Respiratory Health Survey II (n = 210, 30 to 53 years of age, 50% males) exposed to CS, a significant increase in the percentage of participants with chronic sputum was observed in those harboring at least one allele with a long (GT)(n) in the HO-1 promoter gene (33 repeats), which is associated with a low level of HO-1 protein expression, compared with those with a short number of (GT)n repeats (21.7% versus 8.6%, P = 0.047). No such results were observed in those who had never smoked (n = 297). We conclude that HO-1 has a significant protective effect against airway mucus hypersecretion in animals and humans exposed to CS.

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 aggression (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 (FEV1) and FEV1/forced ventilatory capacity (FVC) ratio. We compared long (L) allele carriers ((GT)(n) > or =33 repeats for one or two alleles) to non-carriers. Cross sectionally, in 2000, L allele carriers showed lower FEV1/FVC than non-carriers. During the 8 year period, the mean annual FEV1 and FEV1/FVC declines were -30.9 (31.1) ml/year and -1.8 (6.1) U/year, respectively. FEV1/FVC decline was steeper in L allele carriers than in non-carriers (-2.6 (5.5) v -1.5 (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 (> or =20 cigarettes/day) only (p for interaction = 0.07 and 0.002 respectively). Baseline heavy smokers carrying the L allele showed the steepest FEV1 decline (-62.0 (29.5 ml/year) and the steepest FEV1/FVC decline (-8.8 (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.

Background Endothelin-1 (EDN1) has been involved in the development of airway obstruction and inflammation in asthma. Several polymorphisms have been identified among the genes encoding for preproET1, an inactive precursor of ET-1, and for ETA (EDNRA) and ETB (EDNRB), the two receptors for EDN1. In the present work, we hypothesised that molecular variation in these genes could be a major determinant of the degree of bronchial obstruction. The purpose of this study was to investigate whether the genetic polymorphisms of preproET-1, EDNRA and EDNRB genes were associated with the degree of airway obstruction, assessed by FEV1. Methods Polymorphisms of preproET-1, EDNRA and EDNRB were first studied in a population of adult asthmatic patients. Results were confirmed in a large population of adults from the general population from the ECRHS II study. Results In our population of adult asthmatic patients, the EDNRB-30G>A (Leu277Leu) polymorphism (GG genotype) is strongly associated with a low FEV1 and with a higher percentage of patients with FEV1 < 80% of predicted value. No relationship was found between pulmonary function and EDNRA-1363C>T (His323His) or preproET-1-595G>T (Lys198Asp) polymorphism. In the adult population from the ECRHS II, we found a similar association between GG genotype and a low FEV1 or a higher percentage of subjects with FEV1 < 80% predicted, especially in the subgroups of asthmatics subjects (OR = 4.31 (95%CI 1.03 – 18.04)) and smokers (OR = 7.42 (95%CI 1.69 – 32.6)). Conclusion the EDNRB-30G>A polymorphism could be a determinant of airway obstruction in humans with predisposing factors such as tobacco smoke exposure or asthma.

Introduction Heme oxygenase (HO1) acts against oxidants which are thought to play a major role in the pathogenesis of chro-nic obstructive pulmonary disease (COPD), characterised by impaired lung function. A (GT)n repeat polymorphism in the HO1 gene promoter can modulate the gene transcription in res-ponse to oxidative stress (Am J Hum Genet 2000 ; 66 : 187-95). We hypothesised that this polymorphism could be associated with the level of lung function and decline in subjects exposed to oxidative agression (smokers). Methods We genotyped 749 French subjects (20-44 yrs, 50% men, 40% never-smokers) examined in both 1992 and 2000 as part of the ECRHS. Lung function was assessed by FEV1 (Forced Expiratory Volume in 1 second) and FEV1/FVC (Forced Ventilatory Capacity) ratio. We compared long (L)-allele carriers ((GT)n > 33 repeats for one or two alleles) to non-carriers. Results Cross-sectionaly, in 2000, L-allele carriers showed lower FEV1/FVC than non-carriers. During the 8-yr period, the mean annual FEVl decline and FEV1/FVC decline were-30.9 ± 31.1 ml/yr and -1.8 ± 6.1%/yr, respectively. FEV1/FVC decline was steeper in L-allele carriers than in non-carriers (-2.6 + 5-5 vs -1.5 ±6.4, p = 0.07). There was a strong interaction between allele L and smoking. In 2000, allele L was associated with lower FEV1 and FEV1/FVC in heavy smokers (≥ 20 cig/day) only (p for interaction=0.07 and 0.002 respectively). Baseline heavy smokers carrying allele L showed the steepest FEV1 decline (-62.0 ± 29.5 ml/yr) and the steepest FEV1/FVC decline (-8.8 ± 5.4%/yr) (p for interaction=0.009 and 0.0006). Conclusions These results suggest that long (L) HO1 gene promoter is associated with susceptibility to airways obstruction espe-cially in heavy smokers.