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Background: Severe α₁-antitrypsin deficiency is a known genetic risk factor for COPD. Heterozygous (protease inhibitor [PI] MZ) individuals have moderately reduced serum levels of α₁-antitrypsin, but whether they have an increased risk of COPD is uncertain.Methods: We compared PI MZ and PI MM individuals in two large populations: a case-control study from Norway (n = 1,669) and a multicenter family-based study from Europe and North America (n = 2,707). We sought to determine whether PI MZ was associated with the specific COPD-related phenotypes of lung function and quantitative CT scan measurements of emphysema and airway disease.Results: PI MZ was associated with a 3.5% lower FEV₁/FVC ratio in the case-control study (P = .035) and 3.9% lower FEV₁/vital capacity (VC) ratio in the family study (P = .009). In the case-control study, PI MZ also was associated with 3.7% more emphysema on quantitative analysis of chest CT scans (P = .003). The emphysema result was not replicated in the family study. PI MZ was not associated with airway wall thickness or COPD status in either population. Among subjects with low smoking exposure (< 20 pack-years), PI MZ individuals had more severe emphysema on chest CT scan than PI MM individuals in both studies.Conclusions: Compared with PI MM individuals, PI MZ heterozygotes had lower FEV₁/(F)VC ratio in two independent studies. Our results suggest that PI MZ individuals may be slightly more susceptible to the development of airflow obstruction than PI MM individuals. [ABSTRACT FROM AUTHOR]

Hypoxemia is a major complication of chronic obstructive pulmonary disease (COPD) that correlates with disease prognosis. Identifying genetic variants associated with oxygenation may provide clues for deciphering the heterogeneity in prognosis among patients with COPD. However, previous genetic studies have been restricted to investigating COPD candidate genes for association with hypoxemia. To report results from the first genome-wide association study (GWAS) of resting oxygen saturation (as measured by pulse oximetry [Spo2]) in subjects with COPD, we performed a GWAS of Spo2 in two large, well characterized COPD populations: COPDGene, including both the non-Hispanic white (NHW) and African American (AA) groups, and Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). We identified several suggestive loci (P < 1 × 10(-5)) associated with Spo2 in COPDGene in the NHW (n = 2810) and ECLIPSE (n = 1758) groups, and two loci on chromosomes 14 and 15 in the AA group (n = 820) from COPDGene achieving a level of genome-wide significance (P < 5 × 10(-8)). The chromosome 14 single-nucleotide polymorphism, rs6576132, located in an intergenic region, was nominally replicated (P < 0.05) in the NHW group from COPDGene. The chromosome 15 single-nucleotide polymorphisms were rare in subjects of European ancestry, so the results could not be replicated. The chromosome 15 region contains several genes, including TICRR and KIF7, and is proximal to RHCG (Rh family C glyocoprotein gene). We have identified two loci associated with resting oxygen saturation in AA subjects with COPD, and several suggestive regions in subjects of European descent with COPD. Our study highlights the importance of investigating the genetics of complex traits in different racial groups.

Background: Increased bronchial responsiveness is characteristic of asthma. Gas cooking, which is a major indoor source of the highly oxidant nitrogen dioxide, has been associated with respiratory symptoms and reduced lung function. However, little is known about the effect of gas cooking on bronchial responsiveness and on how this relationship may be modified by variants in the genes GSTM1, GSTT1 and GSTP1, which influence antioxidant defences., Methods: The study was performed in subjects with forced expiratory volume in one second at least 70% of predicted who took part in the multicentre European Community Respiratory Health Survey, had bronchial responsiveness assessed by methacholine challenge and had been genotyped for GSTM1, GSTT1 and GSTP1-rs1695. Information on the use of gas for cooking was obtained from interviewer-led questionnaires. Effect modification by genotype on the association between the use of gas for cooking and bronchial responsiveness was assessed within each participating country, and estimates combined using meta-analysis., Results: Overall, gas cooking, as compared with cooking with electricity, was not associated with bronchial responsiveness (β=-0.08, 95% CI -0.40 to 0.25, p=0.648). However, GSTM1 significantly modified this effect (β for interaction=-0.75, 95% CI -1.16 to -0.33, p=4×10(-4)), with GSTM1 null subjects showing more responsiveness if they cooked with gas. No effect modification by GSTT1 or GSTP1-rs1695 genotypes was observed., Conclusions: Increased bronchial responsiveness was associated with gas cooking among subjects with the GSTM1 null genotype. This may reflect the oxidant effects on the bronchi of exposure to nitrogen dioxide., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

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 single nucleotide polymorphisms (SNPs) were associated with COPD status, lung function variables, and quantitative computed tomography (CT) measurements of emphysema and airway wall thickness. Furthermore, 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 = .029 and p = .0058). The association with E1 was replicated in the ICGN family study, where the minor allele was associated with more emphysema (p = .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.

Background: The number of female smokers developing chronic obstructive pulmonary disease (COPD) is rapidly increasing, but whether or not there exists a differential susceptibility by gender remains controversial., Methods: How smoking behaviour and subsequent lung function reduction differed by gender was examined in a study including 954 subjects with COPD and 955 subjects without COPD. The study focused on two subgroups: subjects with COPD <60 years of age (early-onset group, n=316) and subjects with COPD with <20 pack-years of smoking (low exposure group, n=241)., Results: In the low exposure group, female subjects with COPD had lower forced expiratory volume in 1 s (FEV(1)) % predicted (48.7% vs 55.8%, p=0.001) and more severe disease (50.4% vs 35.6%, p=0.020, in GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage 3 and 4) than male subjects with COPD. Females also had lower FEV(1)% predicted (50.6% vs 56.0%, p=0.006) and more severe COPD (41.7% vs 31.1% in GOLD stage 3 and 4, p=0.050) in the early-onset group. Using multivariate regression, female gender was associated with 5.7% lower FEV(1)% predicted in the low exposure group (p=0.012) and a similar trend was observed in the early-onset group (p=0.057). The number of pack-years was not significantly associated with lung function in female subjects with COPD in this study, and the dose-response relationship between smoking and lung function differed by gender at lower levels of smoking exposure. Interaction analysis suggested that the effect of smoking on lung function might be different by gender (p=0.027 in all subjects with COPD)., Conclusions: Female gender was associated with lung function reduction and more severe disease in subjects with COPD with early onset of disease or low smoking exposure. The findings may suggest a gender difference in susceptibility to the lung-damaging effects of cigarette smoking, but alternative explanations should be considered.

Introduction: Sampling is regarded as crucial to the validity of case-control studies. Ideally, cases and controls should be selected from the same source population, but deviations from this approach are often seen., Objective: Our objective was to examine how exposure-disease relationships in a study on chronic obstructive pulmonary disease (COPD) were affected by the sampling sources of cases and controls., Methods: A Norwegian case-control study on COPD including 1909 subjects used three sources of recruitment for cases (general population, hospital registry and volunteers) and two sources for controls (general population and volunteers). This resulted in six sampling combinations of cases and controls (groups A-F). We examined how the risk factors gender, age, smoking, educational level and comorbidity were associated with COPD in these six sampling groups., Results: Several exposure-disease associations were dependent on variation in sampling source, thereby demonstrating the possibility of selection bias. The theoretically most ideal sampling group is likely group A, where both cases and controls are recruited from a general population. When using group A as a reference, the groups containing either voluntary controls and/or hospital-based cases deviated the most, suggesting higher susceptibility to selection bias in these groups., Conclusion: Recruitment from several sources made our study design vulnerable to selection bias. Our findings should bring about increased awareness to the sampling process, and encourage sampling of cases and controls from the same source population in future studies.

Aims: Chronic obstructive pulmonary disease (COPD) is a complex disease influenced by multiple genetic and environmental factors. This short communication gives a description of the preliminary genetic results from a case-control study in Bergen, Norway., Methods: A large case-control study in Bergen in 2003-2005 with 6365 invited subjects generated 1954 cases or controls. The overall attendance of invited subjects was 60%, but causes of non-attendance varied considerably among different sources of recruitment., Results: In this case-control study, the candidate gene SERPINE2 on chromosome 2q has demonstrated significant association to COPD. However, only weak or lacking associations have so far been observed for the other candidate genes examined., Conclusion: These findings provide support for SERPINE2 as a COPD susceptibility gene in the Norwegian population.

Background: Smoking and snuff habits among medical students are of interest because they may reflect the attitude to smoking and snuff among future doctors, but few longitudinal studies have been performed., Material and Method: A standard questionnaire, developed by Statistics Norway, was handed out to all medical students at the University of Bergen during plenum lectures in the spring 2004 and 2006. The questionnaires were marked by personal codes to enable follow-up of smoking and snuff habits for each individual student during the study period. New questionnaires were sent by post to all students who did not respond after the initial handout., Results: 799 medical students (89 %) responded in the spring 2004 and 789 students (84 %) in the spring 2006. The study revealed that 3 % of the students smoked regularly in 2004 and 1 % in 2006 and that 20 % were occasional smokers in 2004 and 18 in 2006. 15 % of the students were snuff users in 2004 and this had increased to 24 % in 2006., Interpretation: A decrease was observed in both daily and occasional smokers among medical students in Bergen during the two-year study period. However, the frequency of snuff users increased. The frequency of regular smokers is low, but the number of occasional smokers is higher than in the general population of the same age.