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Surfactant protein D (SFTPD) induces emphysema in knockout mice, but the association of SFTPD with chronic obstructive pulmonary disease (COPD) and emphysema in humans is unclear. Therefore, we aimed to determine the association between genetic variations in SFTPD and susceptibility to COPD and emphysema.

Two populations were studied: population A comprised 270 smokers, including 188 COPD and 82 at-risk subjects, and population B comprised 1131 autopsy cases including 160 cases with emphysema. Six single-nucleotide polymorphisms (SNPs) that tagged the linkage disequilibrium blocks on the entire SFTPD gene were genotyped; the associations of the genotypes with COPD, pulmonary function, percentage of the low-attenuation area (LAA%), and percentage of the airway wall area (WA%) were determined in population A. In population B, the associations of the genotypes with emphysema were assessed.

A C allele at SNP rs721917 that results in the replacement of Met with Thr at position 11 in SFTPD was positively correlated with the LAA% in the upper lung (P=1.1 × 10−5) and overall LAA% (P=1.0 × 10−4), and negatively correlated with the serum concentration of SFTPD (P=7 × 10−11) in the population A. The C/C (rs721917/rs10887199) haplotype was associated with emphysema in both the populations.

Subjects with a C allele at rs721917 have a lower serum SFTPD concentration and are more susceptible to emphysema. This suggests a protective effect of SFTPD against COPD and emphysema.

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.

Author Summary

There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD), which is a heritable multi-factorial trait. Identifying the genetic determinants of COPD risk will have tremendous public health importance. This study describes the first genome-wide association study (GWAS) in COPD. We conducted a GWAS in a homogenous case-control cohort from Norway and evaluated the top 100 single nucleotide polymorphisms in the family-based International COPD Genetics Network. The polymorphisms that showed replication were further evaluated in subjects from the US National Emphysema Treatment Trial and controls from the Normative Aging Study and then in a fourth cohort of extended pedigrees from the Boston Early-Onset COPD population. Two polymorphisms in the α-nicotinic acetylcholine receptor 3/5 locus on chromosome 15 showed unambiguous evidence of association with COPD. This locus has previously been implicated in both smoking behavior and risk of lung cancer, suggesting the possibility of multiple functional polymorphisms in the region or a single polymorphism with wide phenotypic consequences. The hedgehog interacting protein (HHIP) locus on chromosome 4, which is associated with COPD, is also a significant risk locus for COPD.

Rationale: Chronic obstructive pulmonary disease (COPD), characterized by airflow limitation, is a disorder with high phenotypic and genetic heterogeneity. Pulmonary emphysema is a major but variable component of COPD; familial data suggest that different components of COPD, such as emphysema, may be influenced by specific genetic factors.

Objectives: To identify genetic determinants of emphysema assessed through high-resolution chest computed tomography in individuals with COPD.

Methods: We performed a genome-wide association study (GWAS) of emphysema determined from chest computed tomography scans with a total of 2,380 individuals with COPD in three independent cohorts of white individuals from (1) a cohort from Bergen, Norway, (2) the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Study, and (3) the National Emphysema Treatment Trial (NETT). We tested single-nucleotide polymorphism associations with the presence or absence of emphysema determined by radiologist assessment in two of the three cohorts and a quantitative emphysema trait (percentage of lung voxels less than –950 Hounsfield units) in all three cohorts.

Measurements and Main Results: We identified association of a single-nucleotide polymorphism in BICD1 with the presence or absence of emphysema (P = 5.2 × 10−7 with at least mild emphysema vs. control subjects; P = 4.8 × 10−8 with moderate and more severe emphysema vs. control subjects).

Conclusions: Our study suggests that genetic variants in BICD1 are associated with qualitative emphysema in COPD. Variants in BICD1 are associated with length of telomeres, which suggests that a mechanism linked to accelerated aging may be involved in the pathogenesis of emphysema.

Clinical trial registered with www.clinicaltrials.gov (NCT00292552).

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.

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 FEV1 (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.

Background

Hypoxemia, hypercarbia, and pulmonary arterial hypertension are known complications of advanced COPD. We sought to identify genetic polymorphisms associated with these traits in a population of patients with severe COPD from the National Emphysema Treatment Trial (NETT).

Methods

In 389 participants from the NETT Genetics Ancillary Study, single-nucleotide polymorphisms (SNPs) were genotyped in five candidate genes previously associated with COPD susceptibility (EPHX1, SERPINE2, SFTPB, TGFB1, and GSTP1). Linear regression models were used to test for associations among these SNPs and three quantitative COPD-related traits (Pao2, Paco2, and pulmonary artery systolic pressure). Genes associated with hypoxemia were tested for replication in probands from the Boston Early-Onset COPD Study.

Results

In the NETT Genetics Ancillary Study population, SNPs in microsomal epoxide hydrolase (EPHX1) [p = 0.01 to 0.04] and serpin peptidase inhibitor, clade E, member 2 (SERPINE2) [p = 0.04 to 0.008] were associated with hypoxemia. One SNP within surfactant protein B (SFTPB) was associated with pulmonary artery systolic pressure (p = 0.01). In probands from the Boston Early-Onset COPD Study, SNPs in EPHX1 and in SERPINE2 were associated with the requirement for supplemental oxygen.

Conclusions

In participants with severe COPD, SNPs in EPHX1 and SERPINE2 were associated with hypoxemia in two separate study populations, and SNPs from SFTPB were associated with pulmonary artery pressure in the NETT participants.

Introduction

Genetic variability of the pulmonary surfactant proteins A and D may affect clearance of microorganisms and the extent of the inflammatory response. The genes of these collectins (SFTPA1, SFTPA2 and SFTPD) are located in a cluster at 10q21-24. The objective of this study was to evaluate the existence of linkage disequilibrium (LD) among these genes, and the association of variability at these genes with susceptibility and outcome of community-acquired pneumonia (CAP). We also studied the effect of genetic variability on SP-D serum levels.

Methods

Seven non-synonymous polymorphisms of SFTPA1, SFTPA2 and SFTPD were analyzed. For susceptibility, 682 CAP patients and 769 controls were studied in a case-control study. Severity and outcome were evaluated in a prospective study. Haplotypes were inferred and LD was characterized. SP-D serum levels were measured in healthy controls.

Results

The SFTPD aa11-C allele was significantly associated with lower SP-D serum levels, in a dose-dependent manner. We observed the existence of LD among the studied genes. Haplotypes SFTPA1 6A2 (P = 0.0009, odds ration (OR) = 0.78), SFTPA2 1A0 (P = 0.002, OR = 0.79), SFTPA1-SFTPA2 6A2-1A0 (P = 0.0005, OR = 0.77), and SFTPD-SFTPA1-SFTPA2 C-6A2-1A0 (P = 0.00001, OR = 0.62) were underrepresented in patients, whereas haplotypes SFTPA2 1A10 (P = 0.00007, OR = 6.58) and SFTPA1-SFTPA2 6A3-1A (P = 0.0007, OR = 3.92) were overrepresented. Similar results were observed in CAP due to pneumococcus, though no significant differences were now observed after Bonferroni corrections. 1A10 and 6A-1A were associated with higher 28-day and 90-day mortality, and with multi-organ dysfunction syndrome (MODS) and acute respiratory distress syndrome (ARDS) respectively. SFTPD aa11-C allele was associated with development of MODS and ARDS.

Conclusions

Our study indicates that missense single nucleotide polymorphisms and haplotypes of SFTPA1, SFTPA2 and SFTPD are associated with susceptibility to CAP, and that several haplotypes also influence severity and outcome of CAP.

Cachexia, whether assessed by body mass index (BMI) or fat-free mass index (FFMI), affects a significant proportion of patients with chronic obstructive pulmonary disease (COPD), and is an independent risk factor for increased mortality, increased emphysema, and more severe airflow obstruction. The variable development of cachexia among patients with COPD suggests a role for genetic susceptibility. The objective of the present study was to determine genetic susceptibility loci involved in the development of low BMI and FFMI in subjects with COPD. A genome-wide association study (GWAS) of BMI was conducted in three independent cohorts of European descent with Global Initiative for Chronic Obstructive Lung Disease stage II or higher COPD: Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points (ECLIPSE; n = 1,734); Norway-Bergen cohort (n = 851); and a subset of subjects from the National Emphysema Treatment Trial (NETT; n = 365). A genome-wide association of FFMI was conducted in two of the cohorts (ECLIPSE and Norway). In the combined analyses, a significant association was found between rs8050136, located in the first intron of the fat mass and obesity–associated (FTO) gene, and BMI (P = 4.97 × 10−7) and FFMI (P = 1.19 × 10−7). We replicated the association in a fourth, independent cohort consisting of 502 subjects with COPD from COPDGene (P = 6 × 10−3). Within the largest contributing cohort of our analysis, lung function, as assessed by forced expiratory volume at 1 second, varied significantly by FTO genotype. Our analysis suggests a potential role for the FTO locus in the determination of anthropomorphic measures associated with COPD.

Rationale: Chromosome 12p has been linked to chronic obstructive pulmonary disease (COPD) in the Boston Early-Onset COPD Study (BEOCOPD), but a susceptibility gene in that region has not been identified.

Objectives: We used high-density single-nucleotide polymorphism (SNP) mapping to implicate a COPD susceptibility gene and an animal model to determine the potential role of SOX5 in lung development and COPD.

Methods: On chromosome 12p, we genotyped 1,387 SNPs in 386 COPD cases from the National Emphysema Treatment Trial and 424 control smokers from the Normative Aging Study. SNPs with significant associations were then tested in the BEOCOPD study and the International COPD Genetics Network. Based on the human results, we assessed histology and gene expression in the lungs of Sox5−/− mice.

Measurements and Main Results: In the case-control analysis, 27 SNPs were significant at P ≤ 0.01. The most significant SNP in the BEOCOPD replication was rs11046966 (National Emphysema Treatment Trial–Normative Aging Study P = 6.0 × 10−4, BEOCOPD P = 1.5 × 10−5, combined P = 1.7 × 10−7), located 3′ to the gene SOX5. Association with rs11046966 was not replicated in the International COPD Genetics Network. Sox5−/− mice showed abnormal lung development, with a delay in maturation before the saccular stage, as early as E16.5. Lung pathology in Sox5−/− lungs was associated with a decrease in fibronectin expression, an extracellular matrix component critical for branching morphogenesis.

Conclusions: Genetic variation in the transcription factor SOX5 is associated with COPD susceptibility. A mouse model suggests that the effect may be due, in part, to its effects on lung development and/or repair processes.

Case-control studies have successfully identified many significant genetic associations for complex diseases, but lack of replication has been a criticism of case-control genetic association studies in general. We selected 12 candidate genes with reported associations to chronic obstructive pulmonary disease (COPD) and genotyped 29 polymorphisms in a family-based study and in a case-control study. In the Boston Early-Onset COPD Study families, significant associations with quantitative and/or qualitative COPD-related phenotypes were found for the tumor necrosis factor (TNF)-α −308G>A promoter polymorphism (P < 0.02), a coding variant in surfactant protein B (SFTPB Thr131Ile) (P = 0.03), and the (GT)31 allele of the heme oxygenase (HMOX1) promoter short tandem repeat (P = 0.02). In the case-control study, the SFTPB Thr131Ile polymorphism was associated with COPD, but only in the presence of a gene-by-environment interaction term (P = 0.01 for both main effect and interaction). The 30-repeat, but not the 31-repeat, allele of HMOX1 was associated (P = 0.04). The TNF −308G>A polymorphism was not significant. In addition, the microsomal epoxide hydrolase “fast” allele (EPHX1 His139Arg) was significantly associated in the case-control study (P = 0.03). Although some evidence for replication was found for SFTPB and HMOX1, none of the previously published COPD genetic associations was convincingly replicated across both study designs.

Rationale

COPD exacerbations reduce quality of life and increase mortality. Genetic variation may explain the substantial variability seen in exacerbation frequency among COPD subjects with similar lung function. We analyzed whether polymorphisms in five candidate genes previously associated with COPD susceptibility also demonstrate association with COPD exacerbations.

Methods

Eighty-eight single nucleotide polymorphisms in microsomal epoxide hydrolase (EPHX1), transforming growth factor beta 1 (TGFB1), SERPINE2, glutathione S-transferase pi (GSTP1), and surfactant protein B (SFTPB) were genotyped in 389 non-Hispanic white participants in the National Emphysema Treatment Trial. Exacerbations were defined as COPD-related emergency room visits or hospitalizations using Centers for Medicare and Medicaid Services claims data.

Measurements and Main Results

216 subjects (56%) experienced one or more exacerbations during the study period. An SFTPB promoter polymorphism, rs3024791, was associated with COPD exacerbations (p=0.008). Logistic regression models confirmed the association with rs3024791 (p = 0.007). Poisson regression models demonstrated association of multiple SFTPB SNPs with exacerbation rates: rs2118177 (p = 0.006), rs2304566 (p = 0.002), rs1130866 (p = 0.04), and rs3024791 (p = 0.002). Polymorphisms in EPHX1, GSTP1, TGFB1, and SERPINE2 did not demonstrate association with COPD exacerbations.

Conclusions

Variants in SFTPB are associated with COPD susceptibility and COPD exacerbation frequency.

The destruction of elastic fibers has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Emphysema has been described in autosomal dominant cutis laxa, which can be caused by mutations in the elastin gene. Previously, a rare functional mutation in the terminal exon of elastin was found in a case of severe, early-onset COPD. To test the hypothesis that other similar elastin mutations may predispose to COPD, we screened 90 probands from the Boston Early-Onset COPD Study and 90 smoking control subjects from the Normative Aging Study for mutations in elastin exons using high-resolution DNA melt analysis followed by resequencing. Rare nonsynonymous single-nucleotide polymorphisms (SNPs) seen only in cases were examined for segregation with airflow obstruction within pedigrees. Common nonsynonymous SNPs were tested for association with COPD in a family-based analysis of 949 subjects from the Boston Early-Onset COPD Study, and in a case–control analysis in 389 COPD cases from the National Emphysema Treatment Trial and 472 control subjects from the Normative Aging Study. Of 28 elastin variants found, 3 were nonsynonymous SNPs found only in cases. The previously described Gly773Asp mutation was found in another proband. The other two SNPs did not clearly segregate with COPD within families. Two common nonsynonymous SNPs did not demonstrate significant associations in either a family-based or case–control analysis. Exonic SNPs in the elastin gene do not appear to be common risk factors for severe COPD.

Introduction

Chronic obstructive pulmonary disease (COPD) is a disease state characterised by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. Classically, it is thought to be a combination of emphysema and chronic bronchitis, although only one of these may be present in some people with COPD. The main risk factor for the development and deterioration of COPD is smoking.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of maintenance drug treatment in stable COPD? What are the effects of maintenance drug treatment in stable COPD? What are the effects of non-drug interventions in people with stable COPD? We searched: Medline, Embase, The Cochrane Library, and other important databases up to February 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 83 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: alpha1 antitrypsin, antibiotics (prophylactic), anticholinergics (inhaled), beta2 agonists (inhaled), corticosteroids (oral and inhaled), general physical activity enhancement, inspiratory muscle training, maintaining healthy weight, mucolytics, oxygen treatment (long-term domiciliary treatment), peripheral muscle strength training, psychosocial and pharmacological interventions for smoking cessation, pulmonary rehabilitation, and theophylline.

Key Points

The main risk factor for the development and deterioration of chronic obstructive pulmonary disease (COPD) is smoking.

Inhaled anticholinergics and beta2 agonists improve lung function and symptoms and reduce exacerbations in stable COPD compared with placebo. It is unclear whether inhaled anticholinergics or inhaled beta2 agonists are the more consistently effective drug class in the treatment of COPD.Short-acting anticholinergics seem to be associated with a small improvement in quality of life compared with beta2 agonists. Long-acting inhaled anticholinergic drugs may improve lung function compared with long-acting beta2 agonists.Combined treatment with inhaled anticholinergics and beta2 agonists may improve symptoms and lung function and reduce exacerbations compared with either treatment alone, although long-term effects are unknown.

Inhaled corticosteroids reduce exacerbations in COPD and reduce decline in FEV1, but the beneficial effects are small. Oral corticosteroids may improve short-term lung function, but have serious adverse effects. Combined inhaled corticosteroids plus long-acting beta2 agonists improve lung function and symptoms and reduce exacerbations compared with placebo, and may be more effective than either treatment alone.

Long-term domiciliary oxygen treatment may improve survival in people with severe daytime hypoxaemia.

Theophylline may improve lung function compared with placebo, but adverse effects limit their usefulness in stable COPD.

We don't know whether mucolytic drugs, prophylactic antibiotics, or alpha1 antitrypsin improve outcomes in people with COPD compared with placebo.

Combined psychosocial and pharmacological interventions for smoking cessation can slow the deterioration of lung function, but have not been shown to reduce long-term mortality compared with usual care.

Multi-modality pulmonary rehabilitation and exercises can improve exercise capacity in people with stable COPD, but nutritional supplementation has not been shown to be beneficial.

Two recent metaanalyses of genome-wide association studies conducted by the CHARGE and SpiroMeta consortia identified novel loci yielding evidence of association at or near genome-wide significance (GWS) with FEV1 and FEV1/FVC. We hypothesized that a subset of these markers would also be associated with chronic obstructive pulmonary disease (COPD) susceptibility. Thirty-two single-nucleotide polymorphisms (SNPs) in or near 17 genes in 11 previously identified GWS spirometric genomic regions were tested for association with COPD status in four COPD case-control study samples (NETT/NAS, the Norway case-control study, ECLIPSE, and the first 1,000 subjects in COPDGene; total sample size, 3,456 cases and 1,906 controls). In addition to testing the 32 spirometric GWS SNPs, we tested a dense panel of imputed HapMap2 SNP markers from the 17 genes located near the 32 GWS SNPs and in a set of 21 well studied COPD candidate genes. Of the previously identified GWS spirometric genomic regions, three loci harbored SNPs associated with COPD susceptibility at a 5% false discovery rate: the 4q24 locus including FLJ20184/INTS12/GSTCD/NPNT, the 6p21 locus including AGER and PPT2, and the 5q33 locus including ADAM19. In conclusion, markers previously associated at or near GWS with spirometric measures were tested for association with COPD status in data from four COPD case-control studies, and three loci showed evidence of association with COPD susceptibility at a 5% false discovery rate.

Patients with chronic obstructive pulmonary disease (COPD) exhibit dominant features of chronic bronchitis, emphysema, and/or asthma, with a common phenotype of airflow obstruction. COPD pulmonary physiology reflects the sum of pathological changes in COPD, which can occur in large central airways, small peripheral airways, and the lung parenchyma. Quantitative or high-resolution computed tomography is used as a surrogate measure for assessment of disease progression. Different biological or molecular markers have been reported that reflect the mechanistic or pathogenic triad of inflammation, proteases, and oxidants and correspond to the different aspects of COPD histopathology. Similar to the pathogenic triad markers, genetic variations or polymorphisms have also been linked to COPD-associated inflammation, protease–antiprotease imbalance, and oxidative stress. Furthermore, in recent years, there have been reports identifying aging-associated mechanistic markers as downstream consequences of the pathogenic triad in the lungs from COPD patients. For this review, the authors have limited their discussion to a review of mechanistic markers and genetic variations and their association with COPD histopathology and disease status.

Rationale: There are no accepted blood-based biomarkers in chronic obstructive pulmonary disease (COPD). Pulmonary and activation-regulated chemokine (PARC/CCL-18) is a lung-predominant inflammatory protein that is found in serum.

Objectives: To determine whether PARC/CCL-18 levels are elevated and modifiable in COPD and to determine their relationship to clinical end points of hospitalization and mortality.

Methods: PARC/CCL-18 was measured in serum samples from individuals who participated in the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) and LHS (Lung Health Study) studies and a prednisolone intervention study.

Measurements and Main Results: Serum PARC/CCL-18 levels were higher in subjects with COPD than in smokers or lifetime nonsmokers without COPD (105 vs. 81 vs. 80 ng/ml, respectively; P < 0.0001). Elevated PARC/CCL-18 levels were associated with increased risk of cardiovascular hospitalization or mortality in the LHS cohort and with total mortality in the ECLIPSE cohort.

Conclusions: Serum PARC/CCL-18 levels are elevated in COPD and track clinical outcomes. PARC/CCL-18, a lung-predominant chemokine, could be a useful blood biomarker in COPD.

Clinical trial registered with www.clinicaltrials.gov (NCT 00292552).

Background

There is a paucity of surrogate lung-specific biological markers that can be used to track disease progression and predict clinical outcomes in chronic obstructive pulmonary disease (COPD). The principal aim of this pilot study was to determine whether circulating surfactant protein D (SPD) or Clara Cell protein-16 (CC16) levels are associated with lung function or health status in patients with severe COPD.

Methods

We studied 23 patients with advanced COPD. Lung function measurements, Chronic Respiratory Disease Questionnaire (CRQ) scores, and serum levels of SPD, CC16, and C-reactive protein (CRP) were determined at baseline and at 3 months.

Results

At baseline, FEV1 was inversely associated with serum SPD levels (P = 0.045) but not with CC16 (P = 0.675) or CRP levels (P = 0.549). Over a 3 month period, changes in SPD levels correlated significantly with changes in CRQ scores (adjusted P = 0.008) such that patients who had the largest declines in serum SPD levels experienced the largest gains in health status. The association was particularly notable between circulating SPD level and the dyspnea domain of the CRQ score (P = 0.018). Changes in CC16 or CRP levels did not correlate with changes in CRQ scores.

Conclusion

Changes in serum SPD levels tracked well with changes in health status over a 3 month period in patients with severe COPD. These data suggest that circulating SPD levels may be useful biomarkers to track health outcomes of COPD patients.

Rationale: Genome-wide association studies have shown significant associations between variants near hedgehog interacting protein HHIP, FAM13A, and cholinergic nicotinic acetylcholine receptor CHRNA3/5 with increased risk of chronic obstructive pulmonary disease (COPD) in smokers; however, the disease mechanisms behind these associations are not well understood.

Objectives: To identify the association between replicated loci and COPD-related phenotypes in well-characterized patient populations.

Methods: The relationship between these three loci and COPD-related phenotypes was assessed in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-point (ECLIPSE) cohort. The results were validated in the family-based International COPD Genetics Network (ICGN).

Measurements and Main Results: The CHRNA3/5 locus was significantly associated with pack-years of smoking (P = 0.002 and 3 × 10−4), emphysema assessed by a radiologist using high-resolution computed tomography (P = 2 × 10−4 and 4.8 × 10−5), and airflow obstruction (P = 0.004 and 1.8 × 10−5) in the ECLIPSE and ICGN populations, respectively. However, variants in the IREB2 gene were only significantly associated with FEV1. The HHIP locus was not associated with smoking intensity but was associated with FEV1/FVC (P = 1.9 × 10−4 and 0.004 in the ECLIPSE and ICGN populations). The HHIP locus was also associated with fat-free body mass (P = 0.007) and with both retrospectively (P = 0.015) and prospectively (P = 0.024) collected COPD exacerbations in the ECLIPSE cohort. Single-nucleotide polymorphisms in the FAM13A locus were associated with lung function.

Conclusions: The CHRNA3/5 locus was associated with increased smoking intensity and emphysema in individuals with COPD, whereas the HHIP and FAM13A loci were not associated with smoking intensity. The HHIP locus was associated with the systemic components of COPD and with the frequency of COPD exacerbations. FAM13A locus was associated with lung function.

Chronic obstructive pulmonary disease (COPD) is a major global health problem and is predicted to become the third most common cause of death by 2020. Apart from the important preventive steps of smoking cessation, there are no other specific treatments for COPD that are as effective in reversing the condition, and therefore there is a need to understand the pathophysiological mechanisms that could lead to new therapeutic strategies. The development of experimental models will help to dissect these mechanisms at the cellular and molecular level. COPD is a disease characterized by progressive airflow obstruction of the peripheral airways, associated with lung inflammation, emphysema and mucus hypersecretion. Different approaches to mimic COPD have been developed but are limited in comparison to models of allergic asthma. COPD models usually do not mimic the major features of human COPD and are commonly based on the induction of COPD-like lesions in the lungs and airways using noxious inhalants such as tobacco smoke, nitrogen dioxide, or sulfur dioxide. Depending on the duration and intensity of exposure, these noxious stimuli induce signs of chronic inflammation and airway remodelling. Emphysema can be achieved by combining such exposure with instillation of tissue-degrading enzymes. Other approaches are based on genetically-targeted mice which develop COPD-like lesions with emphysema, and such mice provide deep insights into pathophysiological mechanisms. Future approaches should aim to mimic irreversible airflow obstruction, associated with cough and sputum production, with the possibility of inducing exacerbations.

Rationale: Patients with severe chronic obstructive pulmonary disease (COPD) may have varying levels of disability despite similar levels of lung function. This variation may reflect different COPD subtypes, which may have different genetic predispositions.

Objectives: To identify genetic associations for COPD-related phenotypes, including measures of exercise capacity, pulmonary function, and respiratory symptoms.

Methods: In 304 subjects from the National Emphysema Treatment Trial, we genotyped 80 markers in 22 positional and/or biologically plausible candidate genes. Regression models were used to test for association, using a test–replication approach to guard against false-positive results. For significant associations, effect estimates were recalculated using the entire cohort. Positive associations with dyspnea were confirmed in families from the Boston Early-Onset COPD Study.

Results: The test–replication approach identified four genes—microsomal epoxide hydrolase (EPHX1), latent transforming growth factor-β binding protein-4 (LTBP4), surfactant protein B (SFTPB), and transforming growth factor-β1 (TGFB1)—that were associated with COPD-related phenotypes. In all subjects, single-nucleotide polymorphisms (SNPs) in EPHX1 (p ⩽ 0.03) and in LTBP4 (p ⩽ 0.03) were associated with maximal output on cardiopulmonary exercise testing. Markers in LTBP4 (p ⩽ 0.05) and SFTPB (p = 0.005) were associated with 6-min walk test distance. SNPs in EPHX1 were associated with carbon monoxide diffusing capacity (p ⩽ 0.04). Three SNPs in TGFB1 were associated with dyspnea (p ⩽ 0.002), one of which replicated in the family study (p = 0.02).

Conclusions: Polymorphisms in several genes seem to be associated with COPD-related traits other than FEV1. These associations may identify genes in pathways important for COPD pathogenesis.

Chronic obstructive pulmonary disease (COPD) is characterized physiologically by expiratory flow limitation and pathologically by alveolar destruction and enlargement and small and large airway inflammation and remodeling. An imbalance between protease and antiprotease activity in the lung is proposed as the major mechanism resulting in emphysema. The imbalance is mostly due to an increase in the numbers of alveolar macrophages and neutrophils. Emphysema can also develop from increased alveolar wall cell death and/or failure in alveolar wall maintenance. Chronic inflammation and increased oxidative stress contribute to increased destruction and/or impaired lung maintenance and repair. Genetic factors may play an important role in disease susceptibility because only a minority of smokers develops emphysema. Recent literature implicates surfactant instability, malnutrition, and alveolar cell apoptosis as possible etiologies. Identification of cellular and molecular mechanisms of COPD pathogenesis is an area of active, ongoing research that may help to determine therapeutic targets for emphysema.

Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are major causes of acute respiratory failure with high rates of morbidity and mortality. Although surfactant protein (SP)-D plays a critical role in pulmonary innate immunity and several clinical studies suggest that this protein may be implicated in the pathophysiology of ARDS, little is known regarding the function of SP-D in ARDS. In the present study, we induced indirect lung injury by intraperitoneal injection of LPS and direct lung injury by intratracheal injection of LPS in wild-type and Sftpd−/− mice to elucidate the role of SP-D during ALI/ARDS. Results indicate that pulmonary levels of IL-6 and TNF-α were higher in Sftpd−/− mice when compared with wild-type mice. However, the magnitude of this difference was 10-fold greater after indirect lung injury compared with direct lung injury. After indirect lung injury, there was a 2-fold increase in the number of pulmonary monocyte/macrophages in the Sftpd−/− mice when compared with wild-type mice, whereas pulmonary neutrophils were not increased. After indirect injury, the concentration of granulocyte-macrophage colony stimulating factor (GM-CSF) was approximately 5-fold greater in Sftpd−/− mice than wild-type mice. In contrast, after direct injury, the concentration of GM-CSF was 20-fold less in Sftpd−/− mice than wild-type mice. Despite increased inflammatory cells and markers of inflammation, survival in Sftpd−/− mice after indirect lung injury was paradoxically increased. In conclusion, these results suggest that SP-D inhibits pulmonary inflammation and migration of peripheral monocyte/macrophages into the lung through GM-CSF–dependent pathways during indirect lung injury.

Airflow limitation in COPD patients is not fully reversible. However, there may be large variability in bronchodilator responsiveness (BDR) among COPD patients, and familial aggregation of BDR suggests a genetic component. Therefore we investigated the association between six candidate genes and BDR in subjects with severe COPD. A total of 389 subjects from the National Emphysema Treatment Trial (NETT) were analyzed. Bronchodilator responsiveness to albuterol was expressed in three ways: absolute change in FEV1, change in FEV1 as a percent of baseline FEV1, and change in FEV1 as a percent of predicted FEV1. Genotyping was completed for 122 single nucleotide polymorphisms (SNPs) in six candidate genes (EPHX1, SFTPB, TGFB1, SERPINE2, GSTP1, ADRB2). Associations between BDR phenotypes and SNP genotypes were tested using linear regression, adjusting for age, sex, pack-years of smoking, and height. Genes associated with BDR phenotypes in the NETT subjects were assessed for replication in 127 pedigrees from the Boston Early-Onset COPD (EOCOPD) Study. Three SNPs in EPHX1 (p = 0.009 – 0.04), three SNPs in SERPINE2 (p = 0.004 – 0.05) and two SNPs in ADRB2 (0.04 – 0.05) were significantly associated with BDR phenotypes in NETT subjects. BDR. One SNP in EPHX1 (rs1009668, p = 0.04) was significantly replicated in EOCOPD subjects. SNPs in SFTPB, TGFB1, and GSTP1 genes were not associated with BDR. In conclusion, a polymorphism of EPHX1 was associated with bronchodilator responsiveness phenotypes in subjects with severe COPD.

Introduction

Chronic obstructive pulmonary disease (COPD) is a leading cause of disability and death. The most common cause of COPD is smoking. There is evidence suggesting that genetic factors influence COPD susceptibility and variants in several candidate genes have been significantly associated with COPD. In this study, we aimed to investigate the possible association of the TNF-α –308, SPB+1580, IL-13 –1055 gene polymorphisms and latent adenovirus C infection with COPD in an Egyptian population.

Material and methods

Our study included 115 subjects (75 smokers with COPD, 25 resistant smokers and 15 non-smokers) who were subjected to spirometric measurements, identification of adenovirus C and genotyping of TNF-α –308G/A, SP-B+1580 C/T and IL-13 –1055 C/T polymorphisms by real-time PCR.

Results

The adenovirus C gene was identified in all subjects. The distribution of TNF-α genotypes showed no significant differences between different groups. However, homozygous A genotype was associated with a significant decrease in FEV1, FEV1/FVC and FEF25/75% of predicted in COPD (p < 0.05). As regards SP-B genotypes, resistant smokers had a significantly higher homozygous T genotype frequency compared to COPD and non smokers (p = 0.005). Interleukin 13 genotypes showed no significant difference between different groups. There was a significant decrease in FEF25/75% of predicted in T allele carriers in COPD patients (p = 0.001).

Conclusions

The COPD is a disease caused by the interaction of combined genes and environmental influences, in the presence of smoking and latent adenovirus C infection, TNF-α –308A, SPB +1580 T and IL-13 –1055 T polymorphisms predispose to the development of COPD.

Rationale: Several family-based studies have identified genetic linkage for lung function and airflow obstruction to chromosome 2q.

Objectives: We hypothesized that merging results of high-resolution single nucleotide polymorphism (SNP) mapping in four separate populations would lead to the identification of chronic obstructive pulmonary disease (COPD) susceptibility genes on chromosome 2q.

Methods: Within the chromosome 2q linkage region, 2,843 SNPs were genotyped in 806 COPD cases and 779 control subjects from Norway, and 2,484 SNPs were genotyped in 309 patients with severe COPD from the National Emphysema Treatment Trial and 330 community control subjects. Significant associations from the combined results across the two case-control studies were followed up in 1,839 individuals from 603 families from the International COPD Genetics Network (ICGN) and in 949 individuals from 127 families in the Boston Early-Onset COPD Study.

Measurements and Main Results: Merging the results of the two case-control analyses, 14 of the 790 overlapping SNPs had a combined P < 0.01. Two of these 14 SNPs were consistently associated with COPD in the ICGN families. The association with one SNP, located in the gene XRCC5, was replicated in the Boston Early-Onset COPD Study, with a combined P = 2.51 × 10−5 across the four studies, which remains significant when adjusted for multiple testing (P = 0.02). Genotype imputation confirmed the association with SNPs in XRCC5.

Conclusions: By combining data from COPD genetic association studies conducted in four independent patient samples, we have identified XRCC5, an ATP-dependent DNA helicase, as a potential COPD susceptibility gene.