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1.  GENETIC ASSOCIATION BETWEEN HUMAN CHITINASES AND LUNG FUNCTION IN COPD 
Human genetics  2011;131(7):1105-1114.
Two primary chitinases have been identified in humans – acid mammalian chitinase (AMCase) and chitotriosidase (CHIT1). Mammalian chitinases have been observed to affect the host’s immune response. The aim of this study was to test for association between genetic variation in the chitinases and phenotypes related to Chronic Obstructive Pulmonary Disease (COPD). Polymorphisms in the chitinase genes were selected based on previous associations with respiratory diseases. Polymorphisms that were associated with lung function level or rate of decline in the Lung Health Study (LHS) cohort were analyzed for association with COPD affection status in four other COPD case-control populations. Chitinase activity and protein levels were also related to genotypes. In the Caucasian LHS population, the baseline forced expiratory volume in one second (FEV1) was significantly different between the AA and GG genotypic groups of the AMCase rs3818822 polymorphism. Subjects with the GG genotype had higher AMCase protein and chitinase activity compared with AA homozygotes. For CHIT1 rs2494303, a significant association was observed between rate of decline in FEV1 and the different genotypes. In the African American LHS population, CHIT1 rs2494303 and AMCase G339T genotypes were associated with rate of decline in FEV1. Although a significant effect of chitinase gene alleles was found on lung function level and decline in the LHS, we were unable to replicate the associations with COPD affection status in the other COPD study groups.
doi:10.1007/s00439-011-1127-1
PMCID: PMC3771523  PMID: 22200767
Chronic Obstructive Pulmonary Disease; chitinase; polymorphism; lung function
2.  The Impact of Nonlinear Smoking Effects on the Identification of Gene-by-Smoking Interactions in COPD Genetics Studies 
Thorax  2010;66(10):903-909.
Background
The identification of gene-by-environment interactions is important to understand the genetic basis of chronic obstructive pulmonary disease (COPD). Many COPD genetic association analyses assume a linear relationship between pack-years of smoking exposure and FEV1; however, this assumption has not been evaluated empirically in cohorts with a wide spectrum of COPD severity.
Methods
We examined the relationship between FEV1 and pack-years of smoking exposure in 4 large cohorts assembled for the purpose of identifying genetic associations with COPD. Using data from the Alpha-1 Antitrypsin Genetic Modifiers Study, we compared the accuracy and power of two different approaches to model smoking by performing a simulation study of a genetic variant with a range of gene-by-smoking interaction effects.
Results
We identified nonlinear relationships between smoking and FEV1 in 4 large cohorts. We demonstrated that in most situations where the relationship between pack-years and FEV1 is nonlinear, a piecewise-linear approach to model smoking and gene-by-smoking interactions is preferable to the commonly used total pack-years approach. We applied the piecewise linear approach to a genetic association analysis of the PI*Z allele in the Norway case-control cohort and identified a potential PI*Z-by-smoking interaction (p=0.03 for FEV1 analysis, p= 0.01 for COPD susceptibility analysis).
Conclusion
In study samples with subjects having a wide range of COPD severity, a nonlinear relationship between pack-years of smoking and FEV1 is likely. In this setting, approaches that account for this nonlinearity can be more powerful and less-biased than the commonly-used approach of using total pack-years to model the smoking effect.
doi:10.1136/thx.2010.146118
PMCID: PMC3312798  PMID: 21163806
smoking; FEV1; gene-by-environment interaction; COPD; gene
3.  Efficacy and safety of 4 weeks' treatment with combined fluticasone furoate/vilanterol in a single inhaler given once daily in COPD: a placebo-controlled randomised trial 
BMJ Open  2012;2(1):e000370.
Background
Fluticasone furoate/vilanterol (FF/VI) is a novel once-daily (OD) inhaled corticosteroid/long-acting β2 agonist combination in development for chronic obstructive pulmonary disease (COPD) and asthma.
Trial design
A multicentre, randomised, double-blind, parallel-group, placebo-controlled study.
Methods
Participants were patients with moderate-to-severe COPD treated with placebo or FF/VI 400/25 μg OD for 4 weeks. Study objectives were to assess the safety and efficacy of FF/VI 400/25 μg OD administered for 4 weeks via a novel dry powder inhaler. Co-primary end points were change from baseline in weighted mean (wm) heart rate 0–4 h postdose at day 28 and the incidence of adverse events (AEs). Secondary end points included change from baseline in trough forced expiratory volume in one second (FEV1) (23–24 h postdose; day 29) and wm FEV1 (0–4 h postdose; day 28). Patients were randomised to receive FF/VI 400/25 μg or placebo in a 2:1 ratio; all patients and investigators were blinded to active or placebo treatment.
Results
60 patients (mean age 64 years) were randomised (FF/VI: n=40; placebo: n=20), and all contributed data to the analysis. Mean screening post-bronchodilator FEV1 per cent predicted was comparable between groups (FF/VI: 58.5%; placebo: 60.1%). The wm heart rate 0–4 h postdose was similar between groups (difference: 0.6 beats per minute; 95% CI −3.9 to 5.1). More on-treatment AEs were reported in the FF/VI group (68%) compared with the placebo group (50%). The most common drug-related AEs in the FF/VI group were oral candidiasis (8%) and dysphonia (5%). There were no clinically relevant effects on laboratory values, including glucose and potassium, or on vital signs or ECGs/Holters. The FF/VI group had statistically greater improvements compared with placebo in trough FEV1 (mean difference 183 ml) and 0–4 h postdose wm FEV1 (mean difference 236 ml).
Conclusion
FF/VI has a good safety and tolerability profile and improves lung function compared with placebo in patients with COPD.
Trial registration number
clinical trials.gov—NCT00731822.
Article summary
Article focus
Is the once-daily inhaled corticosteroid/long-acting β2 agonist (ICS/LABA) combination FF/VI efficacious with a favourable safety and tolerability profile in COPD?
Key messages
In patients with moderate-to-severe COPD, FF/VI 400/25 μg once daily improved lung function. AEs frequently experienced with other ICS/LABA combinations were generally reported at similar frequencies in the placebo and active treatment arms.
Strengths and limitations of this study
This paper is the first to present clinical data on inhaled FF/VI combination therapy in patients with chronic obstructive lung disease. Given the 4-week duration of this study, there was no end point or surrogate marker to specifically address the relative clinical effects of FF in COPD (such as exacerbations), whereas the observed lung function effects are predominantly induced by the LABA component of the combination.
doi:10.1136/bmjopen-2011-000370
PMCID: PMC3263438  PMID: 22267687
4.  POLYMORPHISMS IN THE SUPEROXIDE DISMUTASE-3 GENE ARE ASSOCIATED WITH EMPHYSEMA IN COPD 
COPD  2010;7(4):262-268.
Superoxide dismutase-3 (SOD3) is a major extracellular antioxidant enzyme, and previous studies have indicated a possible role of this gene in chronic obstructive pulmonary disease (COPD). We hypothesized that polymorphisms in the SOD3 gene would be associated with COPD and COPD-related phenotypes.
We genotyped three SOD3 polymorphisms (rs8192287 (E1), rs8192288 (I1) and rs1799895 (R213G)) in a case-control cohort, with severe COPD cases from the National Emphysema Treatment Trial (NETT, n=389) and smoking controls from the Normative Aging Study (NAS, n=472). We examined whether the SNPs were associated with COPD status, lung function variables, and quantitative CT measurements of emphysema and airway wall thickness. Further, we tried to replicate our initial findings in two family-based studies, the International COPD Genetics Network (ICGN, n=3061) and the Boston Early-Onset COPD Study (EOCOPD, n=949).
In NETT COPD cases, the minor alleles of SNPs E1 and I1 were associated with a higher percentage of emphysema (%LAA950) on chest CT scan (p=0.029 and p=0.0058). The association with E1 was replicated in the ICGN family study, where the minor allele was associated with more emphysema (p=0.048). Airway wall thickness was positively associated with the E1 SNP in ICGN; however, this finding was not confirmed in NETT. Quantitative CT data were not available in EOCOPD. The SNPs were not associated with lung function variables or COPD status in any of the populations.
In conclusion, polymorphisms in the SOD3 gene were associated with CT emphysema but not COPD susceptibility, highlighting the importance of phenotype definition in COPD genetics studies.
doi:10.3109/15412555.2010.496821
PMCID: PMC2923920  PMID: 20673035
5.  Swabbing for respiratory viral infections in older patients: a comparison of rayon and nylon flocked swabs 
The purpose of this study was to compare the sampling efficacy of rayon swabs and nylon flocked swabs, and of oropharyngeal and nasopharyngeal specimens for the detection of respiratory viruses in elderly patients. Samples were obtained from patients 60 years of age or above who were newly admitted to Sorlandet Hospital Arendal, Norway. The patients were interviewed for current symptoms of a respiratory tract infection. Using rayon swabs and nylon flocked swabs, comparable sets of mucosal samples were harvested from the nasopharynx and the oropharynx. The samples were analysed using real-time polymerase chain reaction (PCR) methods. A total of 223 patients (mean age 74.9 years, standard deviation [SD] 9.0 years) were swabbed and a virus was recovered from 11% of the symptomatic patients. Regardless of the sampling site, a calculated 4.8 times higher viral load (95% confidence interval [CI] 1.3–17, p = 0.017) was obtained using the nylon flocked swabs as compared to the rayon swabs. Also, regardless of the type of swab, a calculated 19 times higher viral load was found in the samples from the nasopharynx as compared to the oropharynx (95% CI 5.4–67.4, p < 0.001). When swabbing for respiratory viruses in elderly patients, nasopharyngeal rather than oropharyngeal samples should be obtained. Nylon flocked swabs appear to be more efficient than rayon swabs.
doi:10.1007/s10096-010-1064-2
PMCID: PMC3022161  PMID: 20853014
6.  Indoor exposures and respiratory symptoms in a Norwegian community sample 
Thorax  2005;60(11):937-942.
Background: Limited data are available on the effect of a poor indoor climate on the respiratory health of adults. No data are available regarding the contribution of indoor exposures to the burden of respiratory symptoms in the population.
Methods: In 1996–7 a community sample of 3181 adults aged 26–82 years was invited to participate in a survey on indoor climate and respiratory health in Hordaland County, Norway. 2401 subjects agreed to take part. Logistic regression was used to examine the relationship between eight markers of indoor exposure and physician diagnosed asthma and five respiratory symptoms, after adjustment for sex, age, smoking, educational level, smoking habits, pack years, and occupational airborne exposure.
Results: Mould exposure was associated with all the respiratory symptoms; the adjusted odds ratios (OR) varied from 1.6 (95% confidence interval (CI) 1.0 to 2.4) for cough with phlegm to 2.3 (95% CI 1.4 to 3.9) for grade 2 dyspnoea. Keeping a cat or dog in childhood was associated with grade 2 dyspnoea and attacks of dyspnoea, with adjusted ORs of 1.3 (95% CI 1.0 to 1.7) and 1.4 (95% CI 1.1 to 1.8), respectively. Having a fitted carpet in the bedroom was negatively associated with three of the five respiratory symptoms. 3–5% of the frequency of the respiratory symptoms in the study population could be attributed to exposure to visible moulds.
Conclusion: Mould exposure is an independent risk factor for several respiratory symptoms in a general population covering a wide age span, but it makes only a small contribution to the respiratory symptom burden in the population at large.
doi:10.1136/thx.2004.025973
PMCID: PMC1747222  PMID: 16055627
7.  Implications of reversibility testing on prevalence and risk factors for chronic obstructive pulmonary disease: a community study 
Thorax  2005;60(10):842-847.
Background: The Global Initiative for Obstructive Lung Disease (GOLD) has defined chronic obstructive pulmonary disease (COPD) as a post-bronchodilator ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) of <0.7. In the first general population based study to apply post-bronchodilator values, the prevalence and predictors of GOLD defined COPD were assessed and the implications of ß2 agonist reversibility testing examined.
Methods: Based on a random population sample, 2235 subjects (77%) aged 26–82 years performed spirometric tests before and 15 minutes after inhaling 0.3 mg salbutamol.
Results: The prevalence of GOLD defined COPD was 7.0% (95% confidence interval (CI) 5.9 to 8.0). This estimate was 27% lower than COPD defined without bronchodilatation. One percent of the population had severe or very severe COPD. Compared with women, men had 3.1 (95% CI 2.1 to 4.8) times higher odds for COPD. Subjects with a smoking history of more than 20 pack years had an odds ratio (OR) of 6.2 (95% CI 3.4 to 11.0) for COPD relative to never-smokers, while subjects older than 75 years had an OR of 18.0 (95% CI 9.2 to 35.0) relative to those below 45 years. Subjects with primary education only had an OR of 2.8 (95% CI 1.4 to 5.3) compared with those with university education. Subjects with body mass index (BMI) <20 kg/m2 were more likely than subjects with BMI 25–29.9 kg/m2 to have COPD (OR 2.4, 95% CI 1.1 to 5.3). The adjusted proportion of COPD attributable to smoking was 68%.
Conclusions: These results indicate that community programmes on prevention of COPD should focus on anti-smoking, nutritional aspects, and socioeconomic conditions. The effect of ß2 reversibility testing on prevalence estimates of COPD was substantial.
doi:10.1136/thx.2005.043943
PMCID: PMC1747202  PMID: 16085729
8.  Performance of population specific job exposure matrices (JEMs): European collaborative analyses on occupational risk factors for chronic obstructive pulmonary disease with job exposure matrices (ECOJEM) 
OBJECTIVES—To compare the performance of population specific job exposure matrices (JEMs) and self reported occupational exposure with data on exposure and lung function from three European general populations.
METHODS—Self reported occupational exposure (yes or no) and present occupation were recorded in the three general population surveys conducted in France, The Netherlands, and Norway. Analysis was performed on subjects, aged 25-64, who provided good forced expiratory volume in 1 second (FEV1) tracings and whose occupations were performed by at least two people, in the French (6217 men and 5571 women), the Dutch (men from urban (854) and rural (780) areas), and the Norwegian (395 men) surveys. Two population specific JEMs, based on the percentage of subjects who reported themselves exposed in each job, were constructed for each survey and each sex. The first matrix classified jobs into three categories of exposure according to the proportion of subjects who reported themselves exposed in each job (P10-50 JEM, low < 10%, moderate 10-49%, high ⩾ 50%). For the second matrix, a dichotomous variable was constructed to have the same statistical power as the self reported exposure—that is, the exposure prevalence (p) was the same with both exposure assessment methods (Pp JEM). Relations between occupational exposure, as estimated by the two JEMs and self reported exposure, and age, height, city, and smoking adjusted FEV1 score were compared.
RESULTS—Significant associations between occupational exposure estimated by the population specific JEM and lung function were found in the French and the rural Dutch surveys, whereas no significant relation was found with self reported exposure. In populations with few subjects in most jobs, exposure cannot be estimated with sufficient precision by a population specific JEM, which may explain the lack of relation in the Norwegian and the Dutch (urban area) surveys.
CONCLUSION—The population specific JEM, which was easy to construct and cost little, seemed to perform better than crude self reported exposures, in populations with sufficient numbers of subjects per job.


Keywords: job exposure matrix; occupational exposure; lung function
doi:10.1136/oem.57.2.126
PMCID: PMC1739909  PMID: 10711281
9.  Smoking and ulcer perforation 
Gut  1997;41(2):177-180.
Background—The use of ulcerogenic drugs is the only well documented risk factor for peptic ulcer perforation, but accounts for only a quarter of the events. Smoking is a well known risk factor for uncomplicated ulcer disease, and patients with ulcer bleeding have increased death rates from smoking related disorders. 
Aim—To assess the role of smoking in ulcer perforation. 
Subjects—A total of 168 consecutive patients with gastroduodenal ulcer perforation and 4469 control subjects from a population based health survey. 
Methods—The association between ulcer perforation and smoking habits was analysed by logistic regression while adjusting for age and sex. 
Results—Current smoking increased the risk for ulcer perforation 10-fold in the age group 15-74 years (OR 9.7, 95% CI 5.9to 15.8) and there was a highly significant dose-response relationship (p<0.001). The results were similar in men (OR 9.3, 95% CI 4.9to 17) and women (OR 11.6, 95% CI 5.3 to 25), and for gastric (OR 10.5, 95% CI 4.5 to 25) and duodenal (OR 8.6, 95% CI 4.9 to 15.4) ulcer perforation. No increase in risk was found in previous smokers (OR 0.8, 95% CI 0.2 to 2.2). 
Conclusion—Our findings suggest that smoking is a causal factor for ulcer perforation and accounts for a major part of ulcer perforations in the population aged less than 75years. 


Keywords: peptic ulcer perforation; gastric ulcer; duodenal ulcer; smoking; NSAID; risk factor
PMCID: PMC1891466  PMID: 9301495
10.  Transcutaneous abdominal ultrasonography in the staging of lung cancer 
Thorax  1997;52(3):276-280.
BACKGROUND: There is limited information available regarding the relationship between clinical indicators of widespread disease in patients with lung cancer and the findings of transcutaneous ultrasonography. METHODS: A retrospective survey was made of 279 consecutive patients with lung cancer. By reviewing the patients' records the clinical findings were divided into symptoms, signs, and laboratory tests indicative of metastatic disease. All patients had been examined by abdominal ultrasonography. RESULTS: The patients included 19% with small cell carcinoma. The frequency of abdominal metastases by ultrasonography in those with small cell carcinoma was 40%, in the other patients it was 8%. Regardless of histological group, all the 40 patients with abdominal metastases by ultrasonography had at least one clinical category indicative of widespread disease and 38 (95%) had two or all three clinical categories positive. Fifty nine patients had no clinical indicators of metastases and none of these had abdominal metastases by ultrasonography. CONCLUSIONS: The results of this study indicate that abdominal metastases are found in lung cancer patients with clinical findings indicative of widespread disease. No abdominal metastases were found in patients with a negative clinical evaluation. The results indicate that transcutaneous ultrasonography of the abdomen is not necessary in the initial staging if the clinical evaluation is unremarkable. 





PMCID: PMC1758515  PMID: 9093346
11.  Single breath transfer factor for carbon monoxide in an asymptomatic population of never smokers. 
Thorax  1992;47(3):167-173.
BACKGROUND: Data on reference values of transfer factor variables in general populations of asymptomatic never smokers are limited. The aim of this study was to examine the relation between test variables and age, height, haemoglobin concentration and carboxyhaemoglobin concentration. METHODS: Measurements of single breath transfer factor for carbon monoxide (TLCO) were obtained for a randomly selected sample of never smokers in north western Europe who were 18-73 years old and had no respiratory symptoms or disorders. Two recordings of TLCO with a ratio of inspiratory vital capacity to forced vital capacity of greater than 0.09 were obtained by standardised techniques for 304 subjects. RESULTS: The measurement errors expressed as a percentage of the common mean value of TLCO, volume adjusted TLCO (KCO), and alveolar volume (VA) were 4.5%, 4.2%, and 2.4% respectively. Multiple linear regressions showed sex specific effects of height and age on TLCO, and, in addition, of haemoglobin and carboxyhaemoglobin concentrations on KCO. VA was associated with height but not with age. The 5th and 95th centiles for TLCO and KCO in men and women were between 78% and 82% and between 120% and 127%, respectively, of predicted values when age and height were taken into account. CONCLUSION: Reference equations and normal values for transfer test variables in a large healthy population of never smokers are described in relation to age, height, and haemoglobin concentrations. To our knowledge, this is the first report of an association between carboxyhaemoglobin concentrations and KCO in a population of never smoking men and women.
PMCID: PMC1021005  PMID: 1519193
12.  Prevalence of obstructive lung disease in a general population: relation to occupational title and exposure to some airborne agents. 
Thorax  1991;46(12):863-870.
BACKGROUND: The importance of occupational exposure to airborne agents in the development of obstructive disease is uncertain. Studying the relation in a community population has the benefit of reducing the healthy worker effect seen in studies of working populations. METHODS: The prevalence of obstructive lung disease was examined in a Norwegian general population aged 18-73 in a two phased cross sectional survey. In the second phase a stratified sample (n = 1512) of those responding in the first phase was invited for clinical and spirometric examination (attendance rate 84%). Attenders were asked to state all jobs lasting greater than 6 months since leaving school and to say whether they had been exposed to any of seven specific agents and work processes potentially harmful to the lungs. RESULTS: The prevalence of asthma and chronic obstructive lung disease was 2.4% and 5.4%, respectively; spirometric airflow limitation (FEV1/FVC less than 0.7 and FEV1 less than 80% of predicted values) was observed in 4.5% of the population. All jobs were categorised into three groups according to the degree of potential airborne exposure. Having a job with a high degree of airborne exposure increased the sex, age, and smoking adjusted odds ratio for obstructive lung disease (asthma and chronic obstructive lung disease) by 3.6 (95% confidence interval 1.3 to 9.9) compared with having a job without airborne exposure; the association with spirometric airflow limitation was 1.4 (0.3 to 5.2). Occupational exposures to quartz, metal gases, aluminium production and processing, and welding were significantly associated with obstructive lung disease after adjusting for sex, age, and smoking habit, the adjusted odds ratios varying between 2.3 and 2.7. Occupational exposure to quartz and asbestos was significantly related to spirometric airflow limitation in people older than 50. CONCLUSION: Occupational title and exposure to specific agents and work processes may be independent markers of obstructive lung disease in the general population.
PMCID: PMC463489  PMID: 1792631
13.  Postal survey on airborne occupational exposure and respiratory disorders in Norway: causes and consequences of non-response. 
STUDY OBJECTIVE--The aim was to examine causes for non-response in a community survey, and how non-response influences prevalence estimates of some exposure and disease variables, and associations between the variables. DESIGN--This was a cross sectional questionnaire study with two reminder letters. The questionnaire asked for information on smoking habits, occupational airborne exposure and respiratory disorders. SETTING--A random sample of 4992 subjects from the general population aged 15-70 years of Hordaland County, Norway. MAIN RESULTS--The overall response rate was 90%, with a 63% response to the initial letter. The response rates to the first and second reminder letters were 56% and 36% respectively. In 20% of the non-respondents an uncompleted questionnaire was returned with cause for non-response; in two thirds of these the cause for non-response was that the subject was not resident at the mailing address. A home visit to a random sample of 50 urban non-respondents provided further information on 29 subjects. A wrong address at the Central Population Registry and the subject's feeling of lack of personal benefit from a postal survey were the major reasons for non-response. Smokers were late respondents and subjects with respiratory disorders tended to be early respondents. CONCLUSION--The main reasons for non-response were a wrong mailing address and a feeling of lack of personal benefit from responding. Using only the initial letter would have changed the estimated prevalence of smokers from 39% to 35%. Otherwise, the estimated prevalence of the exposure and disease variables as well as the associations between them were only slightly changed after including the respondents to the first and second reminder letters.
PMCID: PMC1060677  PMID: 2277255

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