Amund Gulsvik

International variation in the prevalence of COPD (The BOLD Study): a population-based prevalence study

BACKGROUND Chronic obstructive pulmonary disease (COPD) is a growing cause of morbidity and mortality worldwide, and accurate estimates of the prevalence of this disease are needed to anticipate the future burden of COPD, target key risk factors, and plan for providing COPD-related health services. We aimed to measure the prevalence of COPD and its risk factors and investigate variation across countries by age, sex, and smoking status. METHODS Participants from 12 sites (n=9425) completed postbronchodilator spirometry testing plus questionnaires about respiratory symptoms, health status, and exposure to COPD risk factors. COPD prevalence estimates based on the Global Initiative for Chronic Obstructive Lung Disease staging criteria were adjusted for the target population. Logistic regression was used to estimate adjusted odds ratios (ORs) for COPD associated with 10-year age increments and 10-pack-year (defined as the number of cigarettes smoked per day divided by 20 and multiplied by the number of years that the participant smoked) increments. Meta-analyses provided pooled estimates for these risk factors. FINDINGS The prevalence of stage II or higher COPD was 10.1% (SE 4.8) overall, 11.8% (7.9) for men, and 8.5% (5.8) for women. The ORs for 10-year age increments were much the same across sites and for women and men. The overall pooled estimate was 1.94 (95% CI 1.80-2.10) per 10-year increment. Site-specific pack-year ORs varied significantly in women (pooled OR=1.28, 95% CI 1.15-1.42, p=0.012), but not in men (1.16, 1.12-1.21, p=0.743). INTERPRETATION This worldwide study showed higher levels and more advanced staging of spirometrically confirmed COPD than have typically been reported. However, although age and smoking are strong contributors to COPD, they do not fully explain variations in disease prevalence-other factors also seem to be important. Although smoking cessation is becoming an increasingly urgent objective for an ageing worldwide population, a better understanding of other factors that contribute to COPD is crucial to assist local public-health officials in developing the best possible primary and secondary prevention policies for their regions.

A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci.

There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD). The only known genetic risk factor is severe deficiency of α1-antitrypsin, which is present in 1–2% of individuals with COPD. We conducted a genome-wide association study (GWAS) in a homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls) and evaluated the top 100 single nucleotide polymorphisms (SNPs) in the family-based International COPD Genetics Network (ICGN; 1891 Caucasian individuals from 606 pedigrees) study. The polymorphisms that showed replication were further evaluated in 389 subjects from the US National Emphysema Treatment Trial (NETT) and 472 controls from the Normative Aging Study (NAS) and then in a fourth cohort of 949 individuals from 127 extended pedigrees from the Boston Early-Onset COPD population. Logistic regression models with adjustments of covariates were used to analyze the case-control populations. Family-based association analyses were conducted for a diagnosis of COPD and lung function in the family populations. Two SNPs at the α-nicotinic acetylcholine receptor (CHRNA 3/5) locus were identified in the genome-wide association study. They showed unambiguous replication in the ICGN family-based analysis and in the NETT case-control analysis with combined p-values of 1.48×10−10, (rs8034191) and 5.74×10−10 (rs1051730). Furthermore, these SNPs were significantly associated with lung function in both the ICGN and Boston Early-Onset COPD populations. The C allele of the rs8034191 SNP was estimated to have a population attributable risk for COPD of 12.2%. The association of hedgehog interacting protein (HHIP) locus on chromosome 4 was also consistently replicated, but did not reach genome-wide significance levels. Genome-wide significant association of the HHIP locus with lung function was identified in the Framingham Heart study (Wilk et al., companion article in this issue of PLoS Genetics; doi:10.1371/journal.pgen.1000429). The CHRNA 3/5 and the HHIP loci make a significant contribution to the risk of COPD. CHRNA3/5 is the same locus that has been implicated in the risk of lung cancer.

Variants in FAM13A are associated with chronic obstructive pulmonary disease

We performed a genome-wide association study for chronic obstructive pulmonary disease (COPD) in three population cohorts, including 2,940 cases and 1,380 controls who were current or former smokers with normal lung function. We identified a new susceptibility locus at 4q22.1 in FAM13A and replicated this association in one case-control group (n = 1,006) and two family-based cohorts (n = 3,808) (rs7671167, combined P = 1.2 × 10−11, combined odds ratio in case-control studies 0.76, 95% confidence interval 0.69–0.83).

Prevalence of obstructive lung disease in a general population: relation to occupational title and exposure to some airborne agents.

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.

Comparison of spirometry criteria for the diagnosis of COPD: results from the BOLD study

Published guidelines recommend spirometry to accurately diagnose chronic obstructive pulmonary disease (COPD). However, even spirometry-based COPD prevalence estimates can vary widely. We compared properties of several spirometry-based COPD definitions using data from the international Burden of Obstructive Lung Disease (BOLD)study. 14 sites recruited population-based samples of adults aged ≥40 yrs. Procedures included standardised questionnaires and post-bronchodilator spirometry. 10,001 individuals provided usable data. Use of the lower limit of normal (LLN) forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio reduced the age-related increases in COPD prevalence that are seen among healthy never-smokers when using the fixed ratio criterion (FEV1/FVC <0.7) recommended by the Global Initiative for Chronic Obstructive Lung Disease. The added requirement of an FEV1 either <80% predicted or below the LLN further reduced age-related increases and also led to the least site-to-site variability in prevalence estimates after adjusting for potential confounders. Use of the FEV1/FEV6 ratio in place of the FEV1/FVC yielded similar prevalence estimates. Use of the FEV1/FVC<LLN criterion instead of the FEV1/FVC <0.7 should minimise known age biases and better reflect clinically significant irreversible airflow limitation. Our study also supports the use of the FEV1/FEV6 as a practical substitute for the FEV1/FVC.

Total and specific serum IgE levels in adults: relationship to sex, age and environmental factors

Abstract. We studied total and specific serum IgE levels cross‐sectionally, potential predictors of obstructive lung disease, in a stratified random sample of 18–73‐year‐old adults (n= 1512). The attendance rate was 84%. The total IgE level and prevalences of specific IgE antibodies against house dust mite and cat were higher for men than for women. Specific IgE levels decreased by increasing age, while total IgE decreased in women only. Smokers had a higher IgE level than non‐smokers, while non‐smokers had more often specific IgE antibodies against timothy and birch than smokers. Subjects with occupational dust or gas exposure had a higher total IgE level than unexposcd. The general population prevalences were for specific IgE antibodies against timothy 4.5%, house dust mite 3.2%, birch 2.6%, cat dander 1.6% mould 0.2% and against any of these 7‐6%. In a multivariate analysis age, occupational dust or gas exposure as well as the interaction terms between sex and age and between smoking and paek‐years were independent predictors for total IgE levels. Male sex, young age, never having smoked and the season of the year were independent predictors for having one or more of the five specific IgE antibodies. Subjects with total serum IgE in the highest quintile (≥66 kU/1) had an adjusted odds ratio of 37 (95% confidence interval: 11–120) for having one or more of the specific IgE antibodies examined, compared with those in the lowest quintile (< 5 kU/1). Demographic and environmental factors were thus predictors of total and specific IgE levels in this adult community. These factors should be taken into account when examining relationships between IgE levels, markers of allergy and inflammation, and airways disease.

A genome-wide association study of COPD identifies a susceptibility locus on chromosome 19q13

The genetic risk factors for chronic obstructive pulmonary disease (COPD) are still largely unknown. To date, genome-wide association studies (GWASs) of limited size have identified several novel risk loci for COPD at CHRNA3/CHRNA5/IREB2, HHIP and FAM13A; additional loci may be identified through larger studies. We performed a GWAS using a total of 3499 cases and 1922 control subjects from four cohorts: the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); the Normative Aging Study (NAS) and National Emphysema Treatment Trial (NETT); Bergen, Norway (GenKOLS); and the COPDGene study. Genotyping was performed on Illumina platforms with additional markers imputed using 1000 Genomes data; results were summarized using fixed-effect meta-analysis. We identified a new genome-wide significant locus on chromosome 19q13 (rs7937, OR = 0.74, P = 2.9 × 10(-9)). Genotyping this single nucleotide polymorphism (SNP) and another nearby SNP in linkage disequilibrium (rs2604894) in 2859 subjects from the family-based International COPD Genetics Network study (ICGN) demonstrated supportive evidence for association for COPD (P = 0.28 and 0.11 for rs7937 and rs2604894), pre-bronchodilator FEV(1) (P = 0.08 and 0.04) and severe (GOLD 3&4) COPD (P = 0.09 and 0.017). This region includes RAB4B, EGLN2, MIA and CYP2A6, and has previously been identified in association with cigarette smoking behavior.

Obesity and nocturnal gastro-oesophageal reflux are related to onset of asthma and respiratory symptoms

Several studies have identified obesity as a risk factor for asthma in both children and adults. An increased prevalence of asthma in subjects with gastro-oesophageal reflux (GOR) and obstructive sleep apnoea syndrome has also been reported. The aim of this investigation was to study obesity, nocturnal GOR and snoring as independent risk factors for onset of asthma and respiratory symptoms in a Nordic population. In a 5–10 yr follow-up study of the European Community Respiratory Health Survey in Iceland, Norway, Denmark, Sweden and Estonia, a postal questionnaire was sent to previous respondents. A total of 16,191 participants responded to the questionnaire. Reported onset of asthma, wheeze and night-time symptoms as well as nocturnal GOR and habitual snoring increased in prevalence along with the increase in body mass index (BMI). After adjusting for nocturnal GOR, habitual snoring and other confounders, obesity (BMI >30) remained significantly related to the onset of asthma, wheeze and night-time symptoms. Nocturnal GOR was independently related to the onset of asthma and in addition, both nocturnal GOR and habitual snoring were independently related to onset of wheeze and night-time symptoms. This study adds evidence to an independent relationship between obesity, nocturnal gastro-oesophageal reflux and habitual snoring and the onset of asthma and respiratory symptoms in adults.

Implications of reversibility testing on prevalence and risk factors for chronic obstructive pulmonary disease: a community study

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 β2 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 β2 reversibility testing on prevalence estimates of COPD was substantial.

Parental smoking in childhood and adult obstructive lung disease: results from the European Community Respiratory Health Survey

Background: Early exposure to parental smoking appears to influence the development of the airways and predispose to respiratory symptoms. A study was undertaken to determine whether the consequences of parental smoking could be traced in adulthood. Methods: Information from interviewer-led questionnaires was available for 18 922 subjects aged 20–44 years from random population samples in 37 areas participating in the European Community Respiratory Health Survey. Lung function data were available for 15 901 subjects. Results: In men, father’s smoking in childhood was associated with more respiratory symptoms (ORwheeze 1.13 (95% CI 1.00 to 1.28); never smokers: ORwheeze 1.21 (95% CI 0.96 to 1.50)) and there was a dose-dependent association between number of parents smoking and wheeze (one: OR 1.08 (95% CI 0.94 to 1.24); both: OR 1.24 (95% CI 1.05 to 1.47); ptrend  =  0.010). A reduced ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) was related to father’s smoking (−0.3% (95% CI −0.6 to 0)) and number of parents smoking (ptrend <0.001) among men. In women, mother’s smoking was associated with more respiratory symptoms and poorer lung function (ORwheeze 1.15 (95% CI 1.01 to 1.31), never smokers: ORwheeze 1.21 (95% CI 0.98–1.51); FEV1 −24 ml (95% CI −45 to −3); FEV1/FVC ratio −0.6% (95% CI −0.9 to −0.3)). These effects were possibly accounted for by maternal smoking in pregnancy (ORwheeze 1.39 (95% CI 1.17 to 1.65); FEV1 −23 ml (95% CI −52 to 7); FEV1/FVC ratio −0.9% (95% CI −1.3 to −0.4)) as there was no association with paternal smoking among women (interaction by sex, p<0.05). These results were homogeneous across centres. Conclusion: Both intrauterine and environmental exposure to parental tobacco smoking was related to more respiratory symptoms and poorer lung function in adulthood in this multicultural study. The age window of particular vulnerability appeared to differ by sex, postnatal exposure being important only in men and a role for prenatal exposure being more evident in women.