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1.  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.
PMCID: PMC4680456  PMID: 26722511
Chronic obstructive pulmonary disease (COPD); forced expiratory volume in one second (FEV1); genetic polymorphism; IL1 gene cluster; lung function decline; C-reactive protein
3.  The Relationship between Telomere Length and Mortality in Chronic Obstructive Pulmonary Disease (COPD) 
PLoS ONE  2012;7(4):e35567.
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, FEV1 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 4th 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.
PMCID: PMC3338848  PMID: 22558169
4.  Azithromycin for Prevention of Exacerbations of COPD 
The New England journal of medicine  2011;365(8):689-698.
Acute exacerbations adversely affect patients with chronic obstructive pulmonary disease (COPD). Macrolide antibiotics benefit patients with a variety of inflammatory airway diseases.
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.
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).
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; number, NCT00325897.)
PMCID: PMC3220999  PMID: 21864166
5.  Effect of heme oxygenase-1 polymorphisms on lung function and gene expression 
BMC Medical Genetics  2011;12:117.
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.
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.
PMCID: PMC3180266  PMID: 21902835
Heme oxygenase; polymorphism; chronic obstructive pulmonary disease
6.  Effect of gene environment interactions on lung function and cardiovascular disease in COPD 
The objective of this study was to determine if gene-environment interactions between cigarette smoking and interleukin-6 (IL6), interferon-γ (IFNG), interleukin-1β (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).
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 (FEV1) over 5 years, baseline FEV1, serum protein levels, cardiovascular disease, and interactions with smoking.
The IL6 rs2069825 single nucleotide polymorphism was associated with the rate of decline of prebronchodilator FEV1 (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) FEV1. 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.
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.
PMCID: PMC3144847  PMID: 21814463
gene-environment interactions; interleukin-6; forced expiratory volume in one second; cardiovascular disease; chronic obstructive pulmonary disease
7.  Efficacy of Esomeprazole for Treatment of Poorly Controlled Asthma; a Randomized Controlled Trial 
The New England journal of medicine  2009;360(15):1487-1499.
Gastroesophageal reflux (GER) is common in asthma patients but often has mild or no symptoms. It is not known whether treatment of GER with proton pump inhibitors (PPIs) in poorly-controlled asthmatics without GER symptoms can substantially improve asthma control.
402 asthmatics with inadequate asthma control despite inhaled corticosteroids and absent or minimal GER symptoms were randomly assigned to either esomeprazole 40mg b.i.d. or matching placebo in a parallel-group double-masked clinical trial. Participants were followed for 24 weeks with daily asthma diaries, every 4-week spirometry, and asthma symptom questionnaires. Participants were classified with respect to GER status with ambulatory pH probe monitoring. The primary outcome was the rate of episodes of poor asthma control (EPACs) based on asthma diaries.
Episodes of poor asthma control occurred with similar frequency in the placebo and esomeprazole treatment groups (2.3 vs 2.5 events/person-year, respectively, P=0.66). There was no treatment effect with respect to components of the EPACs, or secondary outcomes including pulmonary function, airways reactivity, asthma control, symptom scores, nocturnal awakenings, or quality of life. GER documented by pH probe studies in 40% of participants with absent or minimal symptoms did not identify a subgroup benefitting from PPI treatment.
Despite a high prevalence of asymptomatic GER in patients with poorly controlled asthma, treatment with proton pump inhibitors does not improve control. Silent GER is not a likely cause of poorly controlled asthma.
PMCID: PMC2974569  PMID: 19357404
8.  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 (NCT00457977).
PMCID: PMC2742743  PMID: 19556517
pneumococcal vaccines; vaccination, COPD; immune responses; immunization
9.  Associations of IL6 polymorphisms with lung function decline and COPD 
Thorax  2009;64(8):698-704.
Interleukin-6 (IL6) is a pleiotropic pro-inflammatory and immunomodulatory cytokine which likely plays an important role in the pathogenesis of COPD. There is a functional single nucleotide polymorphism (SNP), −174G/C, in the promoter region of IL6. We hypothesized that IL6 SNPs influence susceptibility for impaired lung function and COPD in smokers.
Seven and 5 SNPs in IL6 were genotyped in two nested case-control samples derived from the Lung Health Study (LHS) based on phenotypes of rate of decline of forced expiratory volume in one second (FEV1) over 5 years and baseline FEV1 at the beginning of the LHS. Serum IL6 concentrations were measured for all subjects. A partially overlapping panel of 9 IL6 SNPs was genotyped in 389 COPD cases from the National Emphysema Treatment Trial (NETT) and 420 controls from the Normative Aging Study (NAS).
In the LHS, three IL6 SNPs were associated with FEV1 decline (0.023 ≤ P ≤ 0.041 in additive models). Among them the IL6_−174C allele was associated with rapid decline of lung function. The association was more significant in a genotype-based analysis (P = 0.006). In the NETT-NAS study, IL6_−174G/C and four other IL6 SNPs, all of which are in linkage disequilibrium with IL6_−174G/C, were associated with susceptibility to COPD (0.01 ≤ P ≤ 0.04 in additive genetic models).
Our results suggest that the IL6_−174G/C SNP is associated with rapid decline of FEV1 and susceptibility to COPD in smokers.
PMCID: PMC2859187  PMID: 19359268
genetic polymorphism; IL6; forced expiratory volume in one second (FEV1); lung function; chronic obstructive pulmonary disease (COPD)
10.  Airflow obstruction in young adults in Canada 
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.
The sample (n=2962) was drawn from six Canadian sites.
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.
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.
Smoking and asthma, jointly and individually, are major determinants of obstructive disorders in young adults. Bronchial hyper-responsiveness contributes to obstruction in both groups.
PMCID: PMC2676367  PMID: 17551598
Airway obstruction; Obstructive lung disease; Risk factors; Young adults
11.  Contribution of alpha- and beta-defensins to lung function decline and infection in smokers: an association study 
Respiratory Research  2006;7(1):76.
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).
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).
There were no associations between individual polymorphisms or imputed haplotypes and rate of decline in lung function or susceptibility to infection.
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.
PMCID: PMC1523340  PMID: 16700921
12.  Prevalence of asthma symptoms among adults aged 20–44 years in Canada 
Reported prevalence rates of asthma vary within and between countries around the world. These differences suggest environmental factors in addition to genetic factors in the cause of the disease and may provide clues for preventive strategies. We examined the variability of asthma-related symptoms and medication use among adults in 6 sites across Canada (Vancouver, Winnipeg, Hamilton, Montreal, Halifax and Prince Edward Island) and compared our findings with those from sites that had participated in a recent European survey.
We used the same sampling strategy and standardized questionnaire as those used in the European Community Respiratory Health Survey (ECRHS). The 6 Canadian sites were selected to represent different environments with respect to climate, air pollution and occupational exposure. Community-based samples of 3000 to 4000 people aged 20–44 years were randomly selected in each site. Subjects were asked to complete the questionnaire by mail between March 1993 and November 1994. Prevalence rates (and 95% confidence intervals [CIs]) of asthma symptoms, self-reported asthma attacks and use of asthma medication were compared across the Canadian sites and with sites that had participated in the ECRHS.
The overall response rate of those selected to receive the questionnaire was 86.5% (range 74.5%–92.8%). The prevalence rates of most asthma symptoms varied significantly among the Canadian sites. For instance, 21.9% (Montreal) to 30.4% (Halifax) of the men and 24.0% (Vancouver) to 35.2% (Halifax) of the women reported wheezing in the year before the survey. Depending on the site, 4.4% to 6.3% of the men and 5.2% to 9.5% of the women reported an asthma attack in the last year, and 4.0% to 6.1% of the men and 4.9% to 9.7% of the women were currently using asthma medication. Prevalence rates of symptoms, asthma attacks and medication use did not change with age, but they were higher among women than among men. Compared with the results from the ECRHS sites, those from the Canadian sites were among the highest.
Significant variation in the prevalence of asthma symptoms, asthma attacks and use of asthma medication between Canadian sites and international sites suggests environmental influences. Different combinations of factors in different sites may be responsible for the high prevalence rates and should be the subject of further research to guide clinical management and public health intervention.
PMCID: PMC80927  PMID: 11314453

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