Associations of interleukin-1 gene cluster polymorphisms with C-reactive protein concentration and lung function decline in smoking-induced chronic obstructive pulmonary disease.

OBJECTIVE: We reported association of haplotypes formed by IL-1b (IL1B)-511C/T (rs16944) and a variable number of tandem repeats (rs2234663) in intron 3 of IL-1 receptor antagonist (IL1RN) with rate of lung function decline in smoking-induced COPD. The aim of current study was to further investigate this association. METHODS: We genotyped an additional 19 polymorphisms in IL1 cluster (including IL1A, IL1B and IL1RN) in non-Hispanic whites who had the fastest (n = 268) and the slowest (n = 292) decline of FEV1% predicted in the same study. We also analyzed the association of all 21 polymorphisms with serum CRP levels. RESULTS: None of 21 polymorphisms showed significant association with rate of decline of lung function or CRP levels after adjusting for multiple comparisons. Before adjusting for multiple comparisons, only IL1RN_19327 (rs315949) showed significant association with lung function decline (P = 0.03, additive model). The frequencies of genotypes containing the IL1RN_19327A allele were 71.9% and 62.2%, respectively in the fast and slow decline groups (P = 0.02, odds ratio = 1.6, 95% confidence interval = 1.1-2.3); the IL1B_5200 (rs1143633) and rs2234663 in IL1RN were associated with serum CRP levels (P=0.04 and 0.03, respectively). CONCLUSIONS: No single marker was significantly associated with either rate of lung function decline or serum CRP levels.

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

An oxidant-antioxidant imbalance in the lung contributes to the development of chronic obstructive pulmonary disease (COPD) that is caused by a complex interaction of genetic and environmental risk factors. Nuclear erythroid 2-related factor 2 (NFE2L2 or NRF2) is a critical molecule in the lung's defense mechanism against oxidants. We investigated whether polymorphisms in the NFE2L2 pathway affected the rate of decline of lung function in smokers from the Lung Health Study (LHS)(n = 547) and in a replication set, the Vlagtwedde-Vlaardingen cohort (n = 533). We selected polymorphisms in NFE2L2 in genes that positively or negatively regulate NFE2L2 transcriptional activity and in genes that are regulated by NFE2L2. Polymorphisms in 11 genes were significantly associated with rate of lung function decline in the LHS. One of these polymorphisms, rs11085735 in the KEAP1 gene, was previously shown to be associated with the level of lung function in the Vlagtwedde-Vlaardingen cohort but not with decline of lung function. Of the 23 associated polymorphisms in the LHS, only rs634534 in the FOSL1 gene showed a significant association in the Vlagtwedde-Vlaardingen cohort with rate of lung function decline, but the direction of the association was not consistent with that in the LHS. In summary, despite finding several nominally significant polymorphisms in the LHS, none of these associations were replicated in the Vlagtwedde-Vlaardingen cohort, indicating lack of effect of polymorphisms in the NFE2L2 pathway on the rate of decline of lung function.

The relationship between telomere length and mortality in chronic obstructive pulmonary disease (COPD).

Some have suggested that chronic obstructive pulmonary disease (COPD) is a disease of accelerated aging. Aging is characterized by shortening of telomeres. The relationship of telomere length to important clinical outcomes such as mortality, disease progression and cancer in COPD is unknown. Using quantitative polymerase chain reaction (qPCR), we measured telomere length of peripheral leukocytes in 4,271 subjects with mild to moderate COPD who participated in the Lung Health Study (LHS). The subjects were followed for approximately 7.5 years during which time their vital status, FEV(1) and smoking status were ascertained. Using multiple regression methods, we determined the relationship of telomere length to cancer and total mortality in these subjects. We also measured telomere length in healthy "mid-life" volunteers and patients with more severe COPD. The LHS subjects had significantly shorter telomeres than those of healthy "mid-life" volunteers (p<.001). Compared to individuals in the 4(th) quartile of relative telomere length (i.e. longest telomere group), the remaining participants had significantly higher risk of cancer mortality (Hazard ratio, HR, 1.48; p = 0.0324) and total mortality (HR, 1.29; p = 0.0425). Smoking status did not make a significant difference in peripheral blood cells telomere length. In conclusion, COPD patients have short leukocyte telomeres, which are in turn associated increased risk of total and cancer mortality. Accelerated aging is of particular relevance to cancer mortality in COPD.

Influence of lightweight ambulatory oxygen on oxygen use and activity patterns of COPD patients receiving long-term oxygen therapy.

Lightweight ambulatory oxygen devices are provided on the assumptions that they enhance compliance and increase activity, but data to support these assumptions are lacking. We studied 22 patients with severe chronic obstructive pulmonary disease receiving long-term oxygen therapy (14 men, average age = 66.9 y, FEV(1) = 33.6%pred, PaO(2) at rest = 51.7 torr) who were using E-cylinders as their portable oxygen. Subjects were recruited at 5 sites and studied over a 2-week baseline period and for 6 months after randomizing them to either continuing to use 22-lb E-cylinders towed on a cart or to carrying 3.6-lb aluminum cylinders. Utilizing novel electronic devices, ambulatory and stationary oxygen use was monitored continuously over the 2 weeks prior to and the 6 months following randomization. Subjects wore tri-axial accelerometers to monitor physical activity during waking hours for 2-3 weeks prior to, and at 3 and 6 months after, randomization. Seventeen subjects completed the study. At baseline, subjects used 17.2 hours of stationary and 2.5 hours of ambulatory oxygen daily. At 6 months, ambulatory oxygen use was 1.4 ± 1.0 hrs in those randomized to E-cylinders and 1.9 ± 2.4 hrs in those using lightweight oxygen (P = NS). Activity monitoring revealed low activity levels prior to randomization and no significant increase over time in either group. In this group of severe chronic obstructive pulmonary disease patients, providing lightweight ambulatory oxygen did not increase either oxygen use or activity. Future efforts might focus on strategies to encourage oxygen use and enhance activity in this patient group. This trial is registered at ClinicalTrials.gov (NCT003257540).

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

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.

Effect of gene environment interactions on lung function and cardiovascular disease in COPD.

BACKGROUND: The objective of this study was to determine if gene-environment interactions between cigarette smoking and interleukin-6 (IL6), interferon-γ (IFNG), interleukin-1ß (IL1B), or interleukin-1 receptor antagonist (IL1RN) single nucleotide polymorphisms are associated with lung function decline and cardiovascular disease in chronic obstructive pulmonary disease (COPD). METHODS: Single nucleotide polymorphisms (SNPs) in IL6, IFNG, IL1B, and IL1RN were genotyped in the Lung Health Study and correlated with rate of decline of forced expiratory volume in 1 second (FEV(1)) over 5 years, baseline FEV(1), serum protein levels, cardiovascular disease, and interactions with smoking. RESULTS: The IL6 rs2069825 single nucleotide polymorphism was associated with the rate of decline of prebronchodilator FEV(1) (P = 0.049), and was found to have a significant interaction (P = 0.004) with mean number of cigarettes smoked per day. There was also a significant interaction of IFNG rs2069727 with smoking on prebronchodilator (P = 0.008) and postbronchodilator (P =0.01) FEV(1.) The IL6 polymorphism was also associated with cardiovascular disease in heterozygous individuals (P = 0.044), and was found to have a significant interaction with smoking (P = 0.024). None of the genetic variants were associated with their respective serum protein levels. CONCLUSION: The results suggest interactions of IL6 rs2069825 and IFNG rs2069727 single nucleotide polymorphisms with cigarette smoking on measures of lung function. The IL6 rs2069825 single nucleotide polymorphism also interacted with smoking to affect the risk of cardiovascular disease in COPD patients.

Azithromycin for prevention of exacerbations of COPD.

BACKGROUND: Acute exacerbations adversely affect patients with chronic obstructive pulmonary disease (COPD). Macrolide antibiotics benefit patients with a variety of inflammatory airway diseases. METHODS: We performed a randomized trial to determine whether azithromycin decreased the frequency of exacerbations in participants with COPD who had an increased risk of exacerbations but no hearing impairment, resting tachycardia, or apparent risk of prolongation of the corrected QT interval. RESULTS: A total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. The rate of 1-year follow-up was 89% in the azithromycin group and 90% in the placebo group. The median time to the first exacerbation was 266 days (95% confidence interval [CI], 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among participants receiving placebo (P<0.001). The frequency of exacerbations was 1.48 exacerbations per patient-year in the azithromycin group, as compared with 1.83 per patient-year in the placebo group (P=0.01), and the hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P<0.001). The scores on the St. George's Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithromycin group than in the placebo group (a mean [±SD] decrease of 2.8±12.8 vs. 0.6±11.4, P=0.004); the percentage of participants with more than the minimal clinically important difference of -4 units was 43% in the azithromycin group, as compared with 36% in the placebo group (P=0.03). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P=0.04). CONCLUSIONS: Among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects. Although this intervention could change microbial resistance patterns, the effect of this change is not known. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00325897.).

Superior immune response to protein-conjugate versus free pneumococcal polysaccharide vaccine in chronic obstructive pulmonary disease.

RATIONALE: Debate exists about the immunogenicity and protective efficacy of antibodies produced by the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in chronic obstructive pulmonary disease (COPD). The 7-valent diphtheria-conjugated pneumococcal polysaccharide vaccine (PCV7) induces a more robust immune response than PPSV23 in healthy elderly adults. OBJECTIVES: We hypothesized that serotype-specific IgG antibody concentration and functional antibody activity would be superior after PCV7 vaccination compared with PPSV23 in moderate to severe COPD. We also posited that older age and prior PPSV23 vaccination would be associated with reduced vaccine responsiveness. METHODS: One hundred twenty patients with COPD were randomized to PPSV23 (63 subjects) or PCV7 (57 subjects). IgG concentrations were determined by ELISA; functional antibody activity was assayed with a standardized opsonophagocytosis assay and reported as an opsonization killing index (OPK). Increases in serotype-specific IgG and OPK at 1 month post vaccination were compared within and between vaccine groups. MEASUREMENTS AND MAIN RESULTS: Both vaccines were well tolerated. Within each study group, postvaccination IgG and OPK were higher than baseline (P < 0.01) for all serotypes. Adjusted for baseline levels, postvaccination IgG was higher in the PCV7 group than the PPSV23 group for all seven serotypes, reaching statistical significance for five (P < 0.05). PCV7 resulted in a higher OPK for six of seven serotypes (statistically greater for four) compared with PPSV23. In multivariate analyses, younger age, vaccine naivety, and receipt of PCV7 were associated with increased OPK responses. CONCLUSIONS: PCV7 induces a superior immune response at 1 month post vaccination compared with PPSV23 in COPD. Older age and prior PPSV23 reduce vaccine responsiveness. Clinical trial registered with www.clinicaltrials.gov (NCT00457977).

Efficacy of esomeprazole for treatment of poorly controlled asthma.

BACKGROUND: Gastroesophageal reflux is common among patients with asthma but often causes mild or no symptoms. It is not known whether treatment of gastroesophageal reflux with proton-pump inhibitors in patients who have poorly controlled asthma without symptoms of gastroesophageal reflux can substantially improve asthma control. METHODS: In a parallel-group, double-blind trial, we randomly assigned 412 participants with inadequately controlled asthma, despite treatment with inhaled corticosteroids, and with minimal or no symptoms of gastroesophageal reflux to receive either 40 mg of esomeprazole twice a day or matching placebo. Participants were followed for 24 weeks with the use of daily asthma diaries, spirometry performed once every 4 weeks, and questionnaires that asked about asthma symptoms. We used ambulatory pH monitoring to ascertain the presence or absence of gastroesophageal reflux in the participants. The primary outcome was the rate of episodes of poor asthma control, as assessed on the basis of entries in asthma diaries. RESULTS: Episodes of poor asthma control occurred with similar frequency in the placebo and esomeprazole groups (2.3 and 2.5 events per person-year, respectively; P=0.66). There was no treatment effect with respect to individual components of the episodes of poor asthma control or with respect to secondary outcomes, including pulmonary function, airway reactivity, asthma control, symptom scores, nocturnal awakening, or quality of life. The presence of gastroesophageal reflux, which was documented by pH monitoring in 40% of participants with minimal or no symptoms, did not identify a subgroup of patients that benefited from treatment with proton-pump inhibitors. There were fewer serious adverse events among patients receiving esomeprazole than among those receiving placebo (11 vs. 17). CONCLUSIONS: Despite a high prevalence of asymptomatic gastroesophageal reflux among patients with poorly controlled asthma, treatment with proton-pump inhibitors does not improve asthma control. Asymptomatic gastroesophageal reflux is not a likely cause of poorly controlled asthma. (ClinicalTrials.gov number, NCT00069823.)

Airflow obstruction in young adults in Canada.

OBJECTIVE: Airflow obstruction is relatively uncommon in young adults, and may indicate potential for the development of progressive disease. The objective of the present study was to enumerate and characterize airflow obstruction in a random sample of Canadians aged 20 to 44 years. SETTING: The sample (n=2962) was drawn from six Canadian sites. DESIGN: A prevalence study using the European Community Respiratory Health Survey protocol was conducted. Airflow obstruction was assessed by spirometry. Bronchial responsiveness, skin reactivity to allergens and total serum immunoglobulin E were also measured. Logistic regression was used for analysis. RESULTS: Airflow obstruction was observed in 6.4% of the sample, not associated with sex or age. The risk of airflow obstruction increased in patients who had smoked and in patients who had lung trouble during childhood. Adjusted for smoking, the risk of airflow obstruction was elevated for subjects with past and current asthma, skin reactivity to allergens, elevated levels of total immunoglobulin E and bronchial hyper-responsiveness. Of the subjects with airflow obstruction, 21% were smokers with a history of asthma, 50% were smokers without asthma, 12% were nonsmokers with asthma and 17% were nonsmokers with no history of asthma. Bronchial hyper-responsiveness increased the prevalence of airflow obstruction in each of these groups. CONCLUSION: Smoking and asthma, jointly and individually, are major determinants of obstructive disorders in young adults. Bronchial hyper-responsiveness contributes to obstruction in both groups.

Association of Hck genetic polymorphisms with gene expression and COPD.

Polymorphonuclear leukocytes (PMNs) are major effector cells in the chronic airway inflammation in chronic obstructive pulmonary disease (COPD). PMN degranulation is associated with degradation of extracellular matrix and tissue damage. Hck is an essential molecule in the signaling pathway regulating PMN degranulation. We hypothesized that polymorphisms affect the expression level of Hck, which, in turn, modulates PMN mediator release and tissue damage and influences the development of COPD. Here we systematically investigated genetic tag polymorphisms of the Hck gene, Hck mRNA and protein expression pattern in PMNs, and PMN mediator release (myeloperoxidase) in 60 healthy white subjects, and assessed their association with the use of several genetic models. The association of genetic polymorphisms with COPD-related phenotypes was determined in the lung healthy study cohort (LHS). We identified a novel 15 bp insertion/deletion polymorphism (8,656 L/S) in intron 1 of the Hck gene, which was associated with differential expression of Hck protein and PMN myeloperoxidase release. In the LHS cohort, there was significant interaction between the 8,656 L/S polymorphism and smoking on baseline lung function and 8,656 L/S was associated with bronchodilator response. These data suggest that the insertion/deletion polymorphism could be a functional polymorphism of the Hck gene, may contribute to COPD pathogenesis and modify COPD-related phenotypes.

Transforming growth factor-beta1 polymorphisms, airway responsiveness and lung function decline in smokers.

Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation in the airways, parenchyma and vessels, which can cause a structural remodeling with increased fibrosis that narrows and fixes the airway lumen. Transforming growth factor-beta1 (TGF-beta1), a multifunctional growth factor, was reported to be increased in the airways of COPD patients. In this study, we hypothesized that polymorphisms in the TGF-beta1 gene would be associated with an accelerated rate of decline of forced expiratory volume in 1s (FEV(1)). Three polymorphisms, -509 (C-->T), +869 (T-->C) and +915 (G-->C), located in TGF-beta1 gene were genotyped. We determined the prevalence of these polymorphisms in 590 continuing smokers who had the fastest (n=283) and slowest (n=307) rate of decline of lung function from the NHLBI Lung Health Study. There was no association between these TGF-beta1 polymorphisms and the rate of decline of FEV(1), but in a post-hoc analysis the genotype distribution at +869 was significantly different between high and low responders to methacholine (P=0.04). These data suggest that the T-C polymorphism at position +869 in the TGF-beta1 gene contributes to airway hyperresponsiveness, but not to rapid decline of lung function.

Inhaled corticosteroids and mortality in COPD.

STUDY OBJECTIVES: To assess the influence of inhaled corticosteroids (ICSs) on mortality in COPD patients, which is currently a controversial topic. SETTING: Manitoba Health maintains a population-wide research database that includes pharmaceutical information. DESIGN AND PATIENTS: We examined mortality in people 90 to 365 days after hospital discharge for COPD, comparing those persons who received inhaled steroids within 90 days of hospital discharge with those who did not. Cox proportional hazards models were used with adjustments for other respiratory drugs, comorbidities, and physician visits before and after hospital discharge. We also compared mortality in patients who received inhaled steroids with those who received other respiratory drugs, but not inhaled steroids, and those who received neither. Using nested case control analysis, we examined the time of receipt of inhaled steroids in relation to fatal events. RESULTS: In people > 65 years of age, inhaled steroids were associated with a 25% reduction in mortality between 90 and 365 days after hospital discharge, while mortality increased with bronchodilator use, physician visits, age, and comorbidities. The exclusion of people who had also received a diagnosis of asthma or had received inhaled steroids before hospitalization did not change the result. Inhaled steroids were associated with an even larger mortality reduction in people aged 35 to 64 years. People who received bronchodilators but no steroids had higher mortality than people who received no bronchodilators or received both bronchodilators and inhaled steroids. The reduction in all-cause mortality was largely due to the decreased number of cardiovascular deaths. The receipt of inhaled steroids within 30 days of death was protective, but this was not the case for greater time intervals. CONCLUSIONS: Therapy with ICSs reduced mortality in COPD patients; the effect was particularly notable for cardiovascular death and was short term in that it was dependent on recent exposure.

Contribution of alpha- and beta-defensins to lung function decline and infection in smokers: an association study.

BACKGROUND: Alpha-defensins, which are major constituents of neutrophil azurophilic granules, and beta-defensins, which are expressed in airway epithelial cells, could contribute to the pathogenesis of chronic obstructive pulmonary disease by amplifying cigarette smoke-induced and infection-induced inflammatory reactions leading to lung injury. In Japanese and Chinese populations, two different beta-defensin-1 polymorphisms have been associated with chronic obstructive pulmonary disease phenotypes. We conducted population-based association studies to test whether alpha-defensin and beta-defensin polymorphisms influenced smokers' susceptibility to lung function decline and susceptibility to lower respiratory infection in two groups of white participants in the Lung Health Study (275 = fast decline in lung function and 304 = no decline in lung function). METHODS: Subjects were genotyped for the alpha-defensin-1/alpha-defensin-3 copy number polymorphism and four beta-defensin-1 polymorphisms (G-20A, C-44G, G-52A and Val38Ile). RESULTS: There were no associations between individual polymorphisms or imputed haplotypes and rate of decline in lung function or susceptibility to infection. CONCLUSION: These findings suggest that, in a white population, the defensin polymorphisms tested may not be of importance in determining who develops abnormally rapid lung function decline or is susceptible to developing lower respiratory infections.

Interferon gamma polymorphisms and their interaction with smoking are associated with lung function.

Interactions between genetic and environmental determinants are likely to be important in the pathogenesis of chronic obstructive pulmonary disease. We hypothesized that interferon gamma (IFNG) single nucleotide polymorphisms (SNPs) and their interaction with smoking are associated with the rate of decline or level of lung function in smokers. We studied four SNPs in IFNG in 585 non-Hispanic whites (NHW) who had the fastest (n =280) or the slowest (n=305) decline of FEV(1)% predicted selected from among continuous smokers followed for 5 years in the NHLBI Lung Health Study. We also studied 1061 NHW with the lowest (n=530) or the highest (n=531) baseline lung function at the beginning of the LHS. Two SNPs were associated with baseline levels of lung function and the p values were 0.008 for +2197T/C in a dominant model and 0.002 for +5171A/G in a recessive model. However, after adjusting for confounding factors, only +5171A/G was still significant (p=0.001 for the recessive model). In addition, there was a significant genotype and smoking interaction with p=0.006 for the +5171A/G (GG vs.GA + AA) for the baseline lung function. When comparing individuals with GG versus individuals with AG + AA for low lung function, the adjusted odds ratios decreased significantly as pack-years increased. No association was found in the rate of decline study. There was an association between IFNG genotype and baseline of lung function and this association was modified by cigarette smoking.

Physician-diagnosed asthma and allergic rhinitis in Manitoba: 1985-1998.

BACKGROUND: A worldwide increase has been noted in the prevalence of asthma, but the data for other allergic disorders are less consistent. OBJECTIVE: To study 14-year trends in utilization of physician resources for asthma and compare them to trends for allergic rhinitis. METHODS: We studied visits to physicians by Manitoba residents for asthma (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 493) and allergic rhinitis (ICD-9 code 477) between 1985 and 1998. Prevalence and incidence of physician resources utilization were calculated annually for the total population and by age groups. Aggregate statistics and frequency of physician resources utilization were also analyzed. RESULTS: The prevalence and incidence of physician resources utilization for asthma increased more than for allergic rhinitis; differences were most striking in the youngest age groups. In adults, the differences were smaller and changed little with time. Most of the increase in asthma care occurred in children and in people without allergic rhinitis. Overall, 17% of Manitobans were diagnosed as having asthma, and the average asthmatic patient made 6 visits. Approximately 14% had an allergic rhinitis diagnosis, each person being seen twice on average. Coexistence of asthma and allergic rhinitis led to increased physician resources utilization for each of the conditions. CONCLUSIONS: Trends in utilization of physician resources for allergic rhinitis differed strikingly from trends for asthma, particularly in the youngest age group. Asthma and allergic rhinitis affected comparable proportions of the population, but a diagnosis of asthma resulted in much higher utilization of physician resources. The relationship of physician-diagnosed asthma and atopy, as indicated by the diagnosis of allergic rhinitis, appears to have weakened with time in children but not in adults.

Lack of association of human leukocyte antigen-B7 with COPD and rate of decline in lung function.

BACKGROUND: Although variation in the human leukocyte antigen (HLA) locus is associated with various diseases, there have been a limited number of studies that have examined the possible role of HLA in chronic obstructive pulmonary disease (COPD). Only HLA-B7 has been shown to be correlated with low forced expiratory volume in 1s (FEV1) in Caucasians; however, this finding has not been replicated. The aim of this study was to investigate the contribution of the HLA-B7 allele to COPD and to rate of decline of lung function. METHODS: We determined the prevalence of HLA-B7 in a group of COPD patients and a non-obstructed control group of smokers by using a polymerase chain reaction-based genotyping assay. We also determined the prevalence of HLA-B7 in smokers selected from the National Heart Lung and Blood Institute, Lung Health Study for having the fastest and slowest decline of lung function. RESULTS: No significant difference was found in the frequency of HLA-B7 between the COPD and non-obstructed groups. There was also no significant association of HLA-B7 with rate of decline of lung function. CONCLUSION: These data indicate that HLA-B7 does not contribute to COPD or rate of decline of FEV1 in smokers.

The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial.

BACKGROUND: Randomized clinical trials have not yet demonstrated the mortality benefit of smoking cessation. OBJECTIVE: To assess the long-term effect on mortality of a randomly applied smoking cessation program. DESIGN: The Lung Health Study was a randomized clinical trial of smoking cessation. Special intervention participants received the smoking intervention program and were compared with usual care participants. Vital status was followed up to 14.5 years. SETTING: 10 clinical centers in the United States and Canada. PATIENTS: 5887 middle-aged volunteers with asymptomatic airway obstruction. MEASUREMENTS: All-cause mortality and mortality due to cardiovascular disease, lung cancer, and other respiratory disease. INTERVENTION: The intervention was a 10-week smoking cessation program that included a strong physician message and 12 group sessions using behavior modification and nicotine gum, plus either ipratropium or a placebo inhaler. RESULTS: At 5 years, 21.7% of special intervention participants had stopped smoking since study entry compared with 5.4% of usual care participants. After up to 14.5 years of follow-up, 731 patients died: 33% of lung cancer, 22% of cardiovascular disease, 7.8% of respiratory disease other than cancer, and 2.3% of unknown causes. All-cause mortality was significantly lower in the special intervention group than in the usual care group (8.83 per 1000 person-years vs. 10.38 per 1000 person-years; P = 0.03). The hazard ratio for mortality in the usual care group compared with the special intervention group was 1.18 (95% CI, 1.02 to 1.37). Differences in death rates for both lung cancer and cardiovascular disease were greater when death rates were analyzed by smoking habit. LIMITATIONS: Results apply only to individuals with airway obstruction. CONCLUSION: Smoking cessation intervention programs can have a substantial effect on subsequent mortality, even when successful in a minority of participants.

Risk of physician-diagnosed asthma in the first 6 years of life.

OBJECTIVE: The objective of this cohort study was to determine if complications of pregnancy and labor, characteristics at birth, and exposure to infections influence the incidence of asthma in the first 6 years of life. DESIGN: We identified all children born between 1980 and 1990 in the Province of Manitoba, Canada. We used records of physician contacts (inpatient and outpatient) and services of the universal provincial health insurance plan to follow up 170,960 children from birth to the age of 6 years to identify the first diagnosis of asthma. Information on mothers and siblings was also obtained to determine family history of disease and exposure to infections. RESULTS: During the study period, a diagnosis of asthma was made in 14.1% of children by the age of 6 years. The incidence was higher in boys than in girls, in those with family history of allergic diseases. It was higher in urban than in rural areas, and lowest in those born in winter. Asthma was more likely in those with low birth weight and premature birth. Certain congenital abnormalities and complications of pregnancy and labor also increased the risk of asthma. The risk of asthma increased with maternal age. Both upper and lower respiratory infections increased the risk of subsequent asthma, and this effect was more important than exposure to familial respiratory infections, which also tended to increase asthma risk. The risk of asthma decreased with the number of siblings when siblings had a history of allergic disorders. CONCLUSIONS: In addition to genetic influences, intrauterine and labor conditions are determinants of asthma. Exposure to both upper and lower respiratory tract infections increases the risk; these infections do not explain the protective effect associated with the increasing number of siblings.

Glutathione S-transferase variants and their interaction with smoking on lung function.

We studied glutathione S-transferase (GST) polymorphisms in 1,098 whites with the lowest (n = 544, FEV(1) % predicted mean +/- SEM = 62.6 +/- 0.1) and the highest (n = 554, FEV(1) % predicted mean +/- SEM = 91.8 +/- 0.1) lung function at the beginning of the Lung Health Study. Homozygosity for GSTP1 105Val was significantly more frequent in the low- than in the high-function group (13.2 vs. 9.3%) (odds ratio = 1.69, 95% confidence interval [CI] = 1.11-2.61, p = 0.016), after adjustment for confounding variables. Subjects with 105Val homozygotes had higher rates of lung function decline in the high-function group (p = 0.017). The frequencies of GSTM1, GSTT1 null genotypes were similar between the high- and low-function groups, but subjects with the GSTT1 null genotype had a faster decline of lung function in the low-function group (p = 0.032). In addition, there was a significant interaction of GSTT1 genotype and pack-years on lung function. When comparing individuals with GSTT1 null genotype with wild type, the adjusted odds ratio was 3.49 (95% CI, 1.48-8.39, p = 0.005) in mild smokers (< or = 25 pack years). We conclude that GST genotypes are risk factors for rapid decline or low lung function in smokers with mild to moderate airflow obstruction.