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1.  Childhood pneumonia increases risk for chronic obstructive pulmonary disease: the COPDGene study 
Respiratory Research  2015;16(1):115.
Development of adult respiratory disease is influenced by events in childhood. The impact of childhood pneumonia on chronic obstructive pulmonary disease (COPD) is not well defined. We hypothesize that childhood pneumonia is a risk factor for reduced lung function and COPD in adult smokers.
COPD cases and control smokers between 45–80 years old from the United States COPDGene Study were included. Childhood pneumonia was defined by self-report of pneumonia at <16 years. Subjects with lung disease other than COPD or asthma were excluded. Smokers with and without childhood pneumonia were compared on measures of respiratory disease, lung function, and quantitative analysis of chest CT scans.
Of 10,192 adult smokers, 854 (8.4 %) reported pneumonia in childhood. Childhood pneumonia was associated with COPD (OR 1.40; 95 % CI 1.17-1.66), chronic bronchitis, increased COPD exacerbations, and lower lung function: post-bronchodilator FEV1 (69.1 vs. 77.1 % predicted), FVC (82.7 vs. 87.4 % predicted), FEV1/FVC ratio (0.63 vs. 0.67; p < 0.001 for all comparisons). Childhood pneumonia was associated with increased airway wall thickness on CT, without significant difference in emphysema. Having both pneumonia and asthma in childhood further increased the risk of developing COPD (OR 1.85; 95 % CI 1.10-3.18).
Children with pneumonia are at increased risk for future smoking-related lung disease including COPD and decreased lung function. This association is supported by airway changes on chest CT scans. Childhood pneumonia may be an important factor in the early origins of COPD, and the combination of pneumonia and asthma in childhood may pose the greatest risk.
Clinical trials registration, NCT00608764 (Active since January 28, 2008).
Electronic supplementary material
The online version of this article (doi:10.1186/s12931-015-0273-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4578796  PMID: 26392057
2.  The clinical and genetic features of the COPD asthma overlap syndrome 
The European respiratory journal  2014;44(2):341-350.
Individuals with COPD and asthma are an important but poorly characterized group. The genetic determinants of COPD-asthma overlap have not been studied.
Identify clinical features and genetic risk factors for COPD-asthma overlap.
Subjects were current or former smoking non-Hispanic whites (NHW) or African-Americans (AA) with COPD. Overlap subjects reported a history of physician-diagnosed asthma before the age of 40. We compared clinical and radiographic features between COPD and overlap subjects. We performed genome-wide association studies (GWAS) in the NHW and AA populations, and combined these results in a meta-analysis.
More women and African Americans reported a history of asthma. Overlap subjects had more severe and more frequent respiratory exacerbations, less emphysema, and greater airway wall thickness compared to subjects with COPD alone. The NHW GWAS identified SNPs in CSMD1 (rs11779254, P=1.57×10−6) and SOX5(rs59569785, P=1.61×10−6) and the meta-analysis identified SNPs in the gene GPR65 (rs6574978, P=1.18×10−7) associated with COPD-asthma overlap.
Overlap subjects have more exacerbations, less emphysema and more airway disease for any degree of lung function impairment compared to COPD alone. We identified novel genetic variants associated with this syndrome. COPD-asthma overlap is an important syndrome and may require distinct clinical management.
PMCID: PMC4154588  PMID: 24876173
3.  Clinical and Radiographic Correlates of Hypoxemia and Oxygen Therapy in the COPDGene Study 
Respiratory medicine  2011;105(8):1211-1221.
Severe hypoxemia is a major complication of chronic obstructive pulmonary disease (COPD). Long term oxygen therapy is beneficial in hypoxemic COPD patients. However, the clinical and radiographic predictors of hypoxemia and the use of oxygen therapy are not well described. This study aimed to find the correlates of resting hypoxemia and the pattern of oxygen use in moderate to severe COPD patients.
Subjects with GOLD stage II or higher COPD from the first 2500 COPDGene subjects were included in this analysis. All subjects were current or ex-smokers between ages 45 and 80. Severe resting hypoxemia was defined as room air oxygen saturation (SpO2) ≤ 88%. Use of supplemental oxygen therapy was determined by questionnaire.
Eighty-two of 1060 COPD subjects (7.7%) had severe resting hypoxemia. Twenty-one of the 82 (25.6%) were not using continuous supplemental oxygen. Female sex, higher BMI, lower FEV1, and enrollment in Denver were independent risk factors for hypoxemia; emphysema severity on quantitative chest CT scan did not predict hypoxemia. 132 of 971(13.6%) subjects without severe resting hypoxemia were using continuous supplemental oxygen. In non-hypoxemic oxygen users, Denver recruitment, higher BMI, lower FEV1, and more severe dyspnea were associated with the use of continuous oxygen.
A large number of COPD patients without severe hypoxemia were using supplemental oxygen therapy and the pattern of oxygen use was affected by factors other than resting SpO2 and emphysema severity. Longitudinal data will be required to reveal the effects of oxygen therapy in this subgroup.
PMCID: PMC3116986  PMID: 21396809
Hypoxemia; long-term oxygen therapy; COPD; emphysema
4.  SOX5 Is a Candidate Gene for Chronic Obstructive Pulmonary Disease Susceptibility and Is Necessary for Lung Development 
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.
PMCID: PMC3137139  PMID: 21330457
chronic obstructive pulmonary disease; emphysema; knockout mice; lung development; single nucleotide polymorphism
5.  Cluster Analysis in the COPDGene Study Identifies Subtypes of Smokers with Distinct Patterns of Airway Disease and Emphysema 
Thorax  2014;69(5):416-423.
There is notable heterogeneity in the clinical presentation of patients with COPD. To characterize this heterogeneity, we sought to identify subgroups of smokers by applying cluster analysis to data from the COPDGene Study.
We applied a clustering method, k-means, to data from 10,192 smokers in the COPDGene Study. After splitting the sample into a training and validation set, we evaluated three sets of input features across a range of k (user-specified number of clusters). Stable solutions were tested for association with four COPD-related measures and five genetic variants previously associated with COPD at genome-wide significance. The results were confirmed in the validation set.
We identified four clusters that can be characterized as 1) relatively resistant smokers (i.e. no/mild obstruction and minimal emphysema despite heavy smoking), 2) mild upper zone emphysema predominant, 3) airway disease predominant, and 4) severe emphysema. All clusters are strongly associated with COPD-related clinical characteristics, including exacerbations and dyspnea (p<0.001). We found strong genetic associations between the mild upper zone emphysema group and rs1980057 near HHIP, and between the severe emphysema group and rs8034191 in the chromosome 15q region (p<0.001). All significant associations were replicated at p<0.05 in the validation sample (12/12 associations with clinical measures and 2/2 genetic associations).
Cluster analysis identifies four subgroups of smokers that show robust associations with clinical characteristics of COPD and known COPD-associated genetic variants.
PMCID: PMC4004338  PMID: 24563194
6.  Multistudy Fine Mapping of Chromosome 2q Identifies XRCC5 as a Chronic Obstructive Pulmonary Disease Susceptibility Gene 
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.
PMCID: PMC2937234  PMID: 20463177
emphysema; genetic linkage; metaanalysis; single nucleotide polymorphism
Respiratory medicine  2013;108(3):491-499.
As the clinical significance of chronic bronchitis among smokers without airflow obstruction is unclear, we sought to determine morbidity associated with this disorder.
We examined subjects from the COPDGene study and compared those with FEV1/FVC ≥0.70, no diagnosis of asthma and chronic bronchitis as defined as a history of cough and phlegm production for ≥3 months/year for ≥2 years (NCB) to non-obstructed subjects without chronic bronchitis (CB−). Multivariate analysis was used to determine factors associated with and impact of NCB.
We identified 597 NCB and 4,283 CB− subjects. NCB participants were younger (55.4 vs. 57.2 years, p<0.001) with greater tobacco exposure (42.9 vs. 37.8 pack-years, p<0.001) and more often current smokers; more frequently reported occupational exposure to fumes (52.8% vs. 42.2%, p<0.001), dust for ≥1 year (55.3% vs. 42.0%, p<0.001) and were less likely to be currently working. NCB subjects demonstrated worse quality-of-life (SGRQ 35.6 vs. 15.1, p<0.001) and exercise capacity (walk distance 415 vs. 449 m, p<0.001) and more frequently reported respiratory “flare-ups” requiring treatment with antibiotics or steroids (0.30 vs. 0.10 annual events/subject, p<0.001) prior to enrollment and during follow-up (0.34 vs. 0.16 annual events/subject, p<0.001). In multivariate analysis, current smoking, GERD, sleep apnea and occupational exposures were significantly associated with NCB.
While longitudinal data will be needed to determine whether NCB progresses to COPD, NCB patients have poorer quality-of-life, exercise capacity and frequent respiratory events. Beyond smoking cessation interventions, further research is warranted to determine the benefit of other therapeutics in this population.
PMCID: PMC3943716  PMID: 24280543
Cough; quality of life; gastroesophageal reflux; occupational exposure; GERD; tobacco
8.  Quantitative Computed Tomography Measures of Pectoralis Muscle Area and Disease Severity in Chronic Obstructive Pulmonary Disease. A Cross-Sectional Study 
Rationale: Muscle wasting in chronic obstructive pulmonary disease (COPD) is associated with a poor prognosis and is not readily assessed by measures of body mass index (BMI). BMI does not discriminate between relative proportions of adipose tissue and lean muscle and may be insensitive to early pathologic changes in body composition. Computed tomography (CT)–based assessments of the pectoralis muscles may provide insight into the clinical significance of skeletal muscles in smokers.
Objectives: We hypothesized that objective assessment of the pectoralis muscle area on chest CT scans provides information that is clinically relevant and independent of BMI.
Methods: Data from the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) Study (n = 73) were used to assess the relationship between pectoralis muscle area and fat-free mass. We then used data in a subset (n = 966) of a larger cohort, the COPDGene (COPD Genetic Epidemiology) Study, to explore the relationship between pectoralis muscle area and COPD-related traits.
Measurements and Main Results: We first investigated the correlation between pectoralis muscle area and fat-free mass, using data from a subset of participants in the ECLIPSE Study. We then further investigated pectoralis muscle area in COPDGene Study participants and found that higher pectoralis muscle area values were associated with greater height, male sex, and younger age. On subsequent clinical correlation, compared with BMI, pectoralis muscle area was more significantly associated with COPD-related traits, including spirometric measures, dyspnea, and 6-minute-walk distance (6MWD). For example, on average, each 10-cm2 increase in pectoralis muscle area was associated with a 0.8-unit decrease in the BODE (Body mass index, Obstruction, Dyspnea, Exercise) index (95% confidence interval, –1.0 to –0.6; P < 0.001). Furthermore, statistically significant associations between pectoralis muscle area and COPD-related traits remained even after adjustment for BMI.
Conclusions: CT-derived pectoralis muscle area provides relevant indices of COPD morbidity that may be more predictive of important COPD-related traits than BMI. However, the relationship with clinically relevant outcomes such as hospitalization and death requires additional investigation. Pectoralis muscle area is a convenient measure that can be collected in the clinical setting in addition to BMI.
PMCID: PMC4028743  PMID: 24558953
COPD; wasting; pectoral muscle area; imaging
9.  Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis 
The Lancet. Respiratory medicine  2014;2(3):214-225.
The genetic risk factors for susceptibility to chronic obstructive pulmonary disease (COPD) are still largely unknown. Additional genetic variants are likely to be identified by genome-wide association studies in larger cohorts or specific subgroups.
Genome-wide association analysis in COPDGene (non-Hispanic whites and African-Americans) was combined with existing data from the ECLIPSE, NETT/NAS, and GenKOLS (Norway) studies. Analyses were performed both using all moderate-to-severe cases and the subset of severe cases. Top loci not previously described as genome-wide significant were genotyped in the ICGN study, and results combined in a joint meta-analysis.
Analysis of a total of 6,633 moderate-to-severe cases and 5,704 controls confirmed association at three known loci: CHRNA3/CHRNA5/IREB2, FAM13A, and HHIP (10−12 < P < 10−14), and also showed significant evidence of association at a novel locus near RIN3 (overall P, including ICGN = 5•4×10−9). In the severe COPD analysis (n=3,497), the effects at two of three previously described loci were significantly stronger; we also identified two additional loci previously reported to affect gene expression of MMP12 and TGFB2 (overall P = 2•6x10−9 and 8•3×10−9). RIN3 and TGFB2 expression levels were reduced in a set of Lung Tissue Research Consortium COPD lung tissue samples compared with controls.
In a genome-wide study of COPD, we confirmed associations at three known loci and found additional genome-wide significant associations with moderate-to-severe COPD near RIN3 and with severe COPD near MMP12 and TGFB2. Genetic variants, apart from alpha-1 antitrypsin deficiency, increase the risk of COPD. Our analysis of severe COPD suggests additional genetic variants may be identified by focusing on this subgroup.
National Heart, Lung, and Blood Institute; the COPD Foundation through contributions from AstraZeneca, Boehringer Ingelheim, Novartis, and Sepracor; GlaxoSmithKline; Centers for Medicare and Medicaid Services; Agency for Healthcare Research and Quality; US Department of Veterans Affairs.
PMCID: PMC4176924  PMID: 24621683
10.  Transforming Growth Factor-β Receptor-3 Is Associated with Pulmonary Emphysema 
Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome, including emphysema and airway disease. Phenotypes defined on the basis of chest computed tomography (CT) may decrease disease heterogeneity and aid in the identification of candidate genes for COPD subtypes. To identify these genes, we performed genome-wide linkage analysis in extended pedigrees from the Boston Early-Onset COPD Study, stratified by emphysema status (defined by chest CT scans) of the probands, followed by genetic association analysis of positional candidate genes. A region on chromosome 1p showed strong evidence of linkage to lung function traits in families of emphysema-predominant probands in the stratified analysis (LOD score = 2.99 in families of emphysema-predominant probands versus 1.98 in all families). Association analysis in 949 individuals from 127 early-onset COPD pedigrees revealed association for COPD-related traits with an intronic single-nucleotide polymorphism (SNP) in transforming growth factor-β receptor-3 (TGFBR3) (P = 0.005). This SNP was significantly associated with COPD affection status comparing 389 cases from the National Emphysema Treatment Trial to 472 control smokers (P = 0.04), and with FEV1 (P = 0.004) and CT emphysema (P = 0.05) in 3,117 subjects from the International COPD Genetics Network. Gene-level replication of association with lung function was seen in 427 patients with COPD from the Lung Health Study. In conclusion, stratified linkage analysis followed by association testing identified TGFBR3 (betaglycan) as a potential susceptibility gene for COPD. Published human microarray and murine linkage studies have also demonstrated the importance of TGFBR3 in emphysema and lung function, and our group and others have previously found association of COPD-related traits with TGFB1, a ligand for TGFBR3.
PMCID: PMC2742752  PMID: 19131638
betaglycan; chronic obstructive pulmonary disease; computed tomography; linkage; single nucleotide polymorphism
11.  Comorbidities of COPD have a major impact on clinical outcomes, particularly in African Americans 
COPD patients have a great burden of comorbidity. However, it is not well established whether this is due to shared risk factors such as smoking, if they impact patients exercise capacity and quality of life, or whether there are racial disparities in their impact on COPD.
We analyzed data from 10,192 current and ex-smokers with (cases) and without COPD (controls) from the COPDGene® cohort to establish risk for COPD comorbidities adjusted for pertinent covariates. In adjusted models, we examined comorbidities prevalence and impact in African-Americans (AA) and Non-Hispanic Whites (NHW).
Comorbidities are more common in COPD compared to those with normal spirometry (controls), and the risk persists after adjustments for covariates including pack-years smoked. After adjustment for confounders, eight conditions were independently associated with worse exercise capacity, quality of life and dyspnea. There were racial disparities in the impact of comorbidities on exercise capacity, dyspnea and quality of life, presence of osteoarthritis and gastroesophageal reflux disease having a greater negative impact on all three outcomes in AAs than NHWs (p<0.05 for all interaction terms).
Individuals with COPD have a higher risk for comorbidities than controls, an important finding shown for the first time comprehensively after accounting for confounders. Individual comorbidities are associated with worse exercise capacity, quality of life, and dyspnea, in African-Americans compared to non-Hispanic Whites.
PMCID: PMC4329763  PMID: 25695106
COPD; Comorbidities; Race
12.  Genetic Associations With Hypoxemia and Pulmonary Arterial Pressure in COPD* 
Chest  2008;135(3):737-744.
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).
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.
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.
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.
PMCID: PMC2906241  PMID: 19017876
case-control studies; COPD; genetics; phenotype; single-nucleotide polymorphism
13.  Haploinsufficiency of Hedgehog interacting protein causes increased emphysema induced by cigarette smoke through network rewiring 
Genome Medicine  2015;7(1):12.
The HHIP gene, encoding Hedgehog interacting protein, has been implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS), and our subsequent studies identified a functional upstream genetic variant that decreased HHIP transcription. However, little is known about how HHIP contributes to COPD pathogenesis.
We exposed Hhip haploinsufficient mice (Hhip+/-) to cigarette smoke (CS) for 6 months to model the biological consequences caused by CS in human COPD risk-allele carriers at the HHIP locus. Gene expression profiling in murine lungs was performed followed by an integrative network inference analysis, PANDA (Passing Attributes between Networks for Data Assimilation) analysis.
We detected more severe airspace enlargement in Hhip+/- mice vs. wild-type littermates (Hhip+/+) exposed to CS. Gene expression profiling in murine lungs suggested enhanced lymphocyte activation pathways in CS-exposed Hhip+/- vs. Hhip+/+ mice, which was supported by increased numbers of lymphoid aggregates and enhanced activation of CD8+ T cells after CS-exposure in the lungs of Hhip+/-mice compared to Hhip+/+ mice. Mechanistically, results from PANDA network analysis suggested a rewired and dampened Klf4 signaling network in Hhip+/- mice after CS exposure.
In summary, HHIP haploinsufficiency exaggerated CS-induced airspace enlargement, which models CS-induced emphysema in human smokers carrying COPD risk alleles at the HHIP locus. Network modeling suggested rewired lymphocyte activation signaling circuits in the HHIP haploinsufficiency state.
Electronic supplementary material
The online version of this article (doi:10.1186/s13073-015-0137-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4355149  PMID: 25763110
14.  Genome‐wide linkage analysis of pulmonary function in families of children with asthma in Costa Rica 
Thorax  2006;62(3):224-230.
Although asthma is highly prevalent among certain Hispanic subgroups, genetic determinants of asthma and asthma‐related traits have not been conclusively identified in Hispanic populations. A study was undertaken to identify genomic regions containing susceptibility loci for pulmonary function and bronchodilator responsiveness (BDR) in Costa Ricans.
Eight extended pedigrees were ascertained through schoolchildren with asthma in the Central Valley of Costa Rica. Short tandem repeat (STR) markers were genotyped throughout the genome at an average spacing of 8.2 cM. Multipoint variance component linkage analyses of forced expiratory volume in 1 second (FEV1) and FEV1/ forced vital capacity (FVC; both pre‐bronchodilator and post‐bronchodilator) and BDR were performed in these eight families (pre‐bronchodilator spirometry, n = 640; post‐bronchodilator spirometry and BDR, n = 624). Nine additional STR markers were genotyped on chromosome 7. Secondary analyses were repeated after stratification by cigarette smoking.
Among all subjects, the highest logarithm of the odds of linkage (LOD) score for FEV1 (post‐bronchodilator) was found on chromosome 7q34–35 (LOD = 2.45, including the additional markers). The highest LOD scores for FEV1/FVC (pre‐bronchodilator) and BDR were found on chromosomes 2q (LOD = 1.53) and 9p (LOD = 1.53), respectively. Among former and current smokers there was near‐significant evidence of linkage to FEV1/FVC (post‐bronchodilator) on chromosome 5p (LOD = 3.27) and suggestive evidence of linkage to FEV1 on chromosomes 3q (pre‐bronchodilator, LOD = 2.74) and 4q (post‐bronchodilator, LOD = 2.66).
In eight families of children with asthma in Costa Rica, there is suggestive evidence of linkage to FEV1 on chromosome 7q34–35. In these families, FEV1/FVC may be influenced by an interaction between cigarette smoking and a locus (loci) on chromosome 5p.
PMCID: PMC2117166  PMID: 17099076
15.  Identifying a gene expression signature of frequent COPD exacerbations in peripheral blood using network methods 
Exacerbations of chronic obstructive pulmonary disease (COPD), characterized by acute deterioration in symptoms, may be due to bacterial or viral infections, environmental exposures, or unknown factors. Exacerbation frequency may be a stable trait in COPD patients, which could imply genetic susceptibility. Observing the genes, networks, and pathways that are up- and down-regulated in COPD patients with differing susceptibility to exacerbations will help to elucidate the molecular signature and pathogenesis of COPD exacerbations.
Gene expression array and plasma biomarker data were obtained using whole-blood samples from subjects enrolled in the Treatment of Emphysema With a Gamma-Selective Retinoid Agonist (TESRA) study. Linear regression, weighted gene co-expression network analysis (WGCNA), and pathway analysis were used to identify signatures and network sub-modules associated with the number of exacerbations within the previous year; other COPD-related phenotypes were also investigated.
Individual genes were not found to be significantly associated with the number of exacerbations. However using network methods, a statistically significant gene module was identified, along with other modules showing moderate association. A diverse signature was observed across these modules using pathway analysis, marked by differences in B cell and NK cell activity, as well as cellular markers of viral infection. Within two modules, gene set enrichment analysis recapitulated the molecular signatures of two gene expression experiments; one involving sputum from asthma exacerbations and another involving viral lung infections. The plasma biomarker myeloperoxidase (MPO) was associated with the number of recent exacerbations.
A distinct signature of COPD exacerbations may be observed in peripheral blood months following the acute illness. While not predictive in this cross-sectional analysis, these results will be useful in uncovering the molecular pathogenesis of COPD exacerbations.
Electronic supplementary material
The online version of this article (doi:10.1186/s12920-014-0072-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4302028  PMID: 25582225
Network analysis; Chronic obstructive pulmonary disease; Gene expression profiling; Biomarker
16.  National Emphysema Treatment Trial State of the Art 
Although a hereditary contribution to emphysema has been long suspected, severe α1-antitrypsin deficiency remains the only conclusively proven genetic risk factor for chronic obstructive pulmonary disease (COPD). Recently, genome-wide linkage analysis has led to the identification of two promising candidate genes for COPD: TGFB1 and SERPINE2. Like multiple other COPD candidate gene associations, even these positionally identified genes have not been universally replicated across all studies. Differences in phenotype definition may contribute to nonreplication in genetic studies of heterogeneous disorders such as COPD. The use of precisely measured phenotypes, including emphysema quantification on high-resolution chest computed tomography scans, has aided in the discovery of additional genes for clinically relevant COPD-related traits. The use of computed tomography scans to assess emphysema and airway disease as well as newer genetic technologies, including gene expression microarrays and genome-wide association studies, has great potential to detect novel genes affecting COPD susceptibility, severity, and response to treatment.
PMCID: PMC2645324  PMID: 18453360
α1-antitrypsin deficiency; chronic obstructive pulmonary disease; genetic linkage; single-nucleotide polymorphism
17.  Comprehensive Testing of Positionally Cloned Asthma Genes in Two Populations 
Rationale: Replication of gene-disease associations has become a requirement in complex trait genetics.
Objectives: In studies of childhood asthma from two different ethnic groups, we attempted to replicate associations with five potential asthma susceptibility genes previously identified by positional cloning.
Methods: We analyzed two family-based samples ascertained through an asthmatic proband: 497 European-American children from the Childhood Asthma Management Program and 439 Hispanic children from the Central Valley of Costa Rica. We genotyped 98 linkage disequilibrium–tagging single-nucleotide polymorphisms (SNPs) in five genes: ADAM33, DPP10, GPR154 (HUGO name: NPSR1), HLA-G, and the PHF11 locus (includes genes SETDB2 and RCBTB1). SNPs were tested for association with asthma and two intermediate phenotypes: airway hyperresponsiveness and total serum immunoglobulin E levels.
Measurements and Main Results: Despite differing ancestries, linkage disequilibrium patterns were similar in both cohorts. Of the five evaluated genes, SNP-level replication was found only for GPR154 (NPSR1). In this gene, three SNPs were associated with asthma in both cohorts, although the opposite alleles were associated in either study. Weak evidence for locus-level replication with asthma was found in the PHF11 locus, although there was no overlap in the associated SNP across the two cohorts. No consistent associations were observed for the three other genes.
Conclusions: These results provide some further support for the role of genetic variation in GPR154 (NPSR1) and PHF11 in asthma susceptibility and also highlight the challenges of replicating genetic associations in complex traits such as asthma, even for genes identified by linkage analysis.
PMCID: PMC2048676  PMID: 17702965
bronchial hyperreactivity; immunoglobulin E; linkage disequilibrium; NPSR1; single-nucleotide polymorphism
18.  Modifying roles of glutathione S-transferase polymorphisms on the association between cumulative lead exposure and cognitive function 
Neurotoxicology  2013;0:10.1016/j.neuro.2013.08.002.
Glutathione-S-transferase gene (GST) polymorphisms can result in variable ability of these enzymes to remove electrophilic substrates. We investigated whether the GSTP1 Val105 and GSTM1 deletion polymorphisms modify the lead-cognitive function association.
We used repeated measures analysis to compare the association between cumulative lead biomarkers—bone lead measured using K-shell X-Ray Fluorescence—and Mini-Mental State Exam (MMSE) score by GST variants, adjusted for covariates, among Normative Aging Study participants, a Boston-based prospective cohort of men. We had complete data for 698 men (providing 1292 observations) for GSTM1 analyses and 595 men (providing 1142 observations) for GSTP1 analyses.
A 15 μg/g higher tibia lead concentration (interquartile range of tibia lead) was associated with a 0.24 point decrement in MMSE score among GSTP1 Val105 variant carriers, which was significantly stronger than the association among men with only wild-type alleles (p=0.01). The association among GSTP1 Val105 carriers was comparable to that of 3 years of age in baseline MMSE scores. The association between tibia lead and MMSE score appeared progressively steeper in participants with increasingly more GSTP1 Val105 alleles. A modest association between tibia lead and lower MMSE score was seen among participants with the GSTM1 deletion polymorphism. Neither of the glutathione S-transferase variants was independently associated with cognitive function, nor with lead biomarker measures. The results pertaining to patella lead were similar to those observed for tibia lead.
Our results suggest that the GSTP1 Val105 polymorphism confers excess susceptibility to the cognitive effects of cumulative lead exposure.
PMCID: PMC3844089  PMID: 23958642
Lead; Glutathione S-transferase; Cognitive function; Environmental exposure; Gene-environment interaction
19.  Distinct Quantitative Computed Tomography Emphysema Patterns Are Associated with Physiology and Function in Smokers 
Rationale: Emphysema occurs in distinct pathologic patterns, but little is known about the epidemiologic associations of these patterns. Standard quantitative measures of emphysema from computed tomography (CT) do not distinguish between distinct patterns of parenchymal destruction.
Objectives: To study the epidemiologic associations of distinct emphysema patterns with measures of lung-related physiology, function, and health care use in smokers.
Methods: Using a local histogram-based assessment of lung density, we quantified distinct patterns of low attenuation in 9,313 smokers in the COPDGene Study. To determine if such patterns provide novel insights into chronic obstructive pulmonary disease epidemiology, we tested for their association with measures of physiology, function, and health care use.
Measurements and Main Results: Compared with percentage of low-attenuation area less than −950 Hounsfield units (%LAA-950), local histogram-based measures of distinct CT low-attenuation patterns are more predictive of measures of lung function, dyspnea, quality of life, and health care use. These patterns are strongly associated with a wide array of measures of respiratory physiology and function, and most of these associations remain highly significant (P < 0.005) after adjusting for %LAA-950. In smokers without evidence of chronic obstructive pulmonary disease, the mild centrilobular disease pattern is associated with lower FEV1 and worse functional status (P < 0.005).
Conclusions: Measures of distinct CT emphysema patterns provide novel information about the relationship between emphysema and key measures of physiology, physical function, and health care use. Measures of mild emphysema in smokers with preserved lung function can be extracted from CT scans and are significantly associated with functional measures.
PMCID: PMC3863741  PMID: 23980521
emphysema; chronic obstructive pulmonary disease; spiral computed tomography; epidemiology
20.  Non-emphysematous chronic obstructive pulmonary disease is associated with diabetes mellitus 
BMC Pulmonary Medicine  2014;14:164.
Chronic obstructive pulmonary disease (COPD) has been classically divided into blue bloaters and pink puffers. The utility of these clinical subtypes is unclear. However, the broader distinction between airway-predominant and emphysema-predominant COPD may be clinically relevant. The objective was to define clinical features of emphysema-predominant and non-emphysematous COPD patients.
Current and former smokers from the Genetic Epidemiology of COPD Study (COPDGene) had chest computed tomography (CT) scans with quantitative image analysis. Emphysema-predominant COPD was defined by low attenuation area at -950 Hounsfield Units (LAA-950) ≥10%. Non-emphysematous COPD was defined by airflow obstruction with minimal to no emphysema (LAA-950 < 5%).
Out of 4197 COPD subjects, 1687 were classified as emphysema-predominant and 1817 as non-emphysematous; 693 had LAA-950 between 5–10% and were not categorized. Subjects with emphysema-predominant COPD were older (65.6 vs 60.6 years, p < 0.0001) with more severe COPD based on airflow obstruction (FEV1 44.5 vs 68.4%, p < 0.0001), greater exercise limitation (6-minute walk distance 1138 vs 1331 ft, p < 0.0001) and reduced quality of life (St. George’s Respiratory Questionnaire score 43 vs 31, p < 0.0001). Self-reported diabetes was more frequent in non-emphysematous COPD (OR 2.13, p < 0.001), which was also confirmed using a strict definition of diabetes based on medication use. The association between diabetes and non-emphysematous COPD was replicated in the ECLIPSE study.
Non-emphysematous COPD, defined by airflow obstruction with a paucity of emphysema on chest CT scan, is associated with an increased risk of diabetes. COPD patients without emphysema may warrant closer monitoring for diabetes, hypertension, and hyperlipidemia and vice versa.
Trial registration identifiers: COPDGene NCT00608764, ECLIPSE NCT00292552.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2466-14-164) contains supplementary material, which is available to authorized users.
PMCID: PMC4216374  PMID: 25341556
Airway disease; CT scan; Diabetes mellitus; Emphysema; Spirometry
22.  Heritability of Chronic Obstructive Pulmonary Disease and Related Phenotypes in Smokers 
Rationale: Previous studies of chronic obstructive pulmonary disease (COPD) have suggested that genetic factors play an important role in the development of disease. However, single-nucleotide polymorphisms that are associated with COPD in genome-wide association studies have been shown to account for only a small percentage of the genetic variance in phenotypes of COPD, such as spirometry and imaging variables. These phenotypes are highly predictive of disease, and family studies have shown that spirometric phenotypes are heritable.
Objectives: To assess the heritability and coheritability of four major COPD-related phenotypes (measurements of FEV1, FEV1/FVC, percent emphysema, and percent gas trapping), and COPD affection status in smokers of non-Hispanic white and African American descent using a population design.
Methods: Single-nucleotide polymorphisms from genome-wide association studies chips were used to calculate the relatedness of pairs of individuals and a mixed model was adopted to estimate genetic variance and covariance.
Measurements and Main Results: In the non-Hispanic whites, estimated heritabilities of FEV1 and FEV1/FVC were both about 37%, consistent with estimates in the literature from family-based studies. For chest computed tomography scan phenotypes, estimated heritabilities were both close to 25%. Heritability of COPD affection status was estimated as 37.7% in both populations.
Conclusions: This study suggests that a large portion of the genetic risk of COPD is yet to be discovered and gives rationale for additional genetic studies of COPD. The estimates of coheritability (genetic covariance) for pairs of the phenotypes suggest considerable overlap of causal genetic loci.
PMCID: PMC3826281  PMID: 23972146
missing heritability; pleiotropy; pulmonary function; imaging phenotypes; chromosomal partition
23.  The association of plasma biomarkers with computed tomography-assessed emphysema phenotypes 
Respiratory Research  2014;15(1):127.
Chronic obstructive pulmonary disease (COPD) is a phenotypically heterogeneous disease. In COPD, the presence of emphysema is associated with increased mortality and risk of lung cancer. High resolution computed tomography (HRCT) scans are useful in quantifying emphysema but are associated with radiation exposure and high incidence of false positive findings (i.e., nodules). Using a comprehensive biomarker panel, we sought to determine if there was a peripheral blood biomarker signature of emphysema.
114 plasma biomarkers were measured using a custom assay in 588 individuals enrolled in the COPDGene study. Quantitative emphysema measurements included percent low lung attenuation (%LAA) ≤ −950 HU, ≤ − 910 HU and mean lung attenuation at the 15th percentile on lung attenuation curve (LP15A). Multiple regression analysis was performed to determine plasma biomarkers associated with emphysema independent of covariates age, gender, smoking status, body mass index and FEV1. The findings were subsequently validated using baseline blood samples from a separate cohort of 388 subjects enrolled in the Treatment of Emphysema with a Selective Retinoid Agonist (TESRA) study.
Regression analysis identified multiple biomarkers associated with CT-assessed emphysema in COPDGene, including advanced glycosylation end-products receptor (AGER or RAGE, p < 0.001), intercellular adhesion molecule 1 (ICAM, p < 0.001), and chemokine ligand 20 (CCL20, p < 0.001). Validation in the TESRA cohort revealed significant associations with RAGE, ICAM1, and CCL20 with radiologic emphysema (p < 0.001 after meta-analysis). Other biomarkers that were associated with emphysema include CDH1, CDH 13 and SERPINA7, but were not available for validation in the TESRA study. Receiver operating characteristics analysis demonstrated a benefit of adding a biomarker panel to clinical covariates for detecting emphysema, especially in those without severe airflow limitation (AUC 0.85).
Our findings, suggest that a panel of blood biomarkers including sRAGE, ICAM1 and CCL20 may serve as a useful surrogate measure of emphysema, and when combined with clinical covariates, may be useful clinically in predicting the presence of emphysema compared to just using covariates alone, especially in those with less severe COPD. Ultimately biomarkers may shed light on disease pathogenesis, providing targets for new treatments.
Electronic supplementary material
The online version of this article (doi:10.1186/s12931-014-0127-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4198701  PMID: 25306249
COPD; Biomarkers; RAGE; ICAM1; CCL20; Emphysema
24.  Genetic Association Analysis of Functional Impairment in Chronic Obstructive Pulmonary Disease 
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.
PMCID: PMC2662917  PMID: 16456143
dyspnea; emphysema; exercise tolerance; genetic association; pulmonary function tests
25.  Genetic susceptibility for chronic bronchitis in chronic obstructive pulmonary disease 
Respiratory Research  2014;15(1):113.
Chronic bronchitis (CB) is one of the classic phenotypes of COPD. The aims of our study were to investigate genetic variants associated with COPD subjects with CB relative to smokers with normal spirometry, and to assess for genetic differences between subjects with CB and without CB within the COPD population.
We analyzed data from current and former smokers from three cohorts: the COPDGene Study; GenKOLS (Bergen, Norway); and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). CB was defined as having a cough productive of phlegm on most days for at least 3 consecutive months per year for at least 2 consecutive years. CB COPD cases were defined as having both CB and at least moderate COPD based on spirometry. Our primary analysis used smokers with normal spirometry as controls; secondary analysis was performed using COPD subjects without CB as controls. Genotyping was performed on Illumina platforms; results were summarized using fixed-effect meta-analysis.
For CB COPD relative to smoking controls, we identified a new genome-wide significant locus on chromosome 11p15.5 (rs34391416, OR = 1.93, P = 4.99 × 10-8) as well as significant associations of known COPD SNPs within FAM13A. In addition, a GWAS of CB relative to those without CB within COPD subjects showed suggestive evidence for association on 1q23.3 (rs114931935, OR = 1.88, P = 4.99 × 10-7).
We found genome-wide significant associations with CB COPD on 4q22.1 (FAM13A) and 11p15.5 (EFCAB4A, CHID1 and AP2A2), and a locus associated with CB within COPD subjects on 1q23.3 (RPL31P11 and ATF6). This study provides further evidence that genetic variants may contribute to phenotypic heterogeneity of COPD.
Trial registration NCT00608764, NCT00292552
Electronic supplementary material
The online version of this article (doi:10.1186/s12931-014-0113-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4190389  PMID: 25241909
Pulmonary disease; Chronic obstructive; Chronic bronchitis; Genome-wide association study

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