Body composition assessment in chronic obstructive pulmonary disease (COPD) is important, as weight loss and muscular wasting are responsible for low exercise capacity in these patients, and low body mass index (BMI) and fat free mass index (FFMI) are important prognostic factors. Our study aims were: (a) to describe body composition in COPD patients referred to a pulmonary rehabilitation center in Bucharest; (b) to examine the relationships between body composition and disease severity (bronchial obstruction, exercise capacity, quality of life); (c) to test if segmental wasting of lower limbs muscle mass (measured by segmental body composition analysis) correlates with decreased exercise capacity.
Material and methods:
We studied 36 consecutive COPD patients referred to our clinic for pulmonary rehabilitation. Patients performed pulmonary function tests, six minutes walking test (6MWT), and health status was evaluated with COPD Assessment Test (CAT). Body composition measurements were performed by direct segmental multi-frequency bioelectrical impedance analysis (BIA).
This study offers the first data on body composition of Romanian COPD patients
The prevalence of nutritional depletion (defined by low BMI and/or low FFMI) among our COPD patients was 22.2%. Mean FFMI was significantly lower in normal or underweight patients versus overweight or obese patients. Patients with low FFMI had lower exercise capacity at the 6MWT and higher CAT scores than patients with normal FFMI.
Depending on the BMI and FFMI values the patients were divided in four categories: normal, semistarvation, sarcopenia and cachexia. The group of patients with sarcopenia (low FFMI and normal BMI) had the lowest mean MIP (Maximal Inspiratory Pressure), the lowest mean 6MWD (six minutes walking distance) and the higher CAT mean scores among all groups. Exercise capacity was significantly lower in muscular depleted patients (with low skeletal muscle mass index - SSMI). MIP correlated significantly with FFMI and SMMI. No correlations were found between parameters of body composition and FEV1 or CAT. Segmental body composition assessment revealed that unbalanced upper/lower skeletal muscle mass is associated with a lower exercise capacity as measured by 6WMT.
This study offers the first data on body composition of Romanian COPD patients. The prevalence of nutritional depletion is similar to that found in other European studies. No significant correlations were found between FFMI and severity of the disease (bronchial obstruction, distance walked, CAT score). FFMI and SSMI correlated significantly with MIP. Sarcopenic patients had the lowest mean 6MWD, the lowest mean MIP and the highest CAT mean scores. SMMI significantly correlated with 6MWD. Segmental body composition assessment of revealed that "unbalanced" patients had lower results at 6MWT. These results show that body composition evaluation is useful for the assessment of COPD patients referred to pulmonary rehabilitation and should be routinely performed
body composition; chronic obstructive pulmonary disease; pulmonary rehabilitation
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).
emphysema; chronic obstructive pulmonary disease; BICD1; single-nucleotide polymorphism
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.
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.
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.
Body composition is an important parameter for patients with chronic obstructive pulmonary disease (COPD) whereas the association between asthma and obesity is not fully understood. The impact of severe refractory asthma (SRA) on fat free mass (FFM) has not been investigated.
Methodology and Principal Findings
213 subjects (70 healthy smokers, 71 COPD patients and 72 asthma patients) without significant comorbidities were included in the study. In all patients, body composition assessment (using bioelectrical impendance analysis, skinfold and anthropometric measurements) and spirometry were performed. Differences in fat free mass index (FFMI) between groups were assessed and determinants of FFMI in asthma were evaluated. Patients with SRA had lower values of FFMI compared to patients with mild-to-moderate asthma [18.0(17.3–18.3)–19.5(18.4–21.5), p<0.001], despite the fact that they were more obese. The levels of FFMI in SRA were lower than those of GOLD stage I–III COPD and comparable to those of stage IV COPD patients [18.0(17.3–18.3)–18.8(17.8–20.1), p = ns]. These differences were present even after proper adjustments for sex, age, smoking status, daily dose of inhaled corticosteroids (ICS) and daily use of oral corticosteroids (OCS). In multivariate analysis, independent predictors of FFMI in asthmatic patients were age, use of OCS and the presence of SRA, but not smoking, sex or cumulative dose of ICS used.
Conclusions and Significance
SRA is related to the presence of low FFMI that is comparable to that of GOLD stage IV COPD. The impact of this observation on asthma mechanisms and outcomes should be further investigated in large prospective studies.
Chronic Obstructive Pulmonary Disease (COPD) has significant systemic effects beyond the lungs amongst which muscle wasting is a prominent contributor to exercise limitation and an independent predictor of morbidity and mortality. The molecular mechanisms leading to skeletal muscle dysfunction/wasting are not fully understood and are likely to be multi-factorial. The need to develop therapeutic strategies aimed at improving skeletal muscle dysfunction/wasting requires a better understanding of the molecular mechanisms responsible for these abnormalities. Microarrays are powerful tools that allow the investigation of the expression of thousands of genes, virtually the whole genome, simultaneously. We aim at identifying genes and molecular pathways involved in skeletal muscle wasting in COPD.
We assessed and compared the vastus lateralis transcriptome of COPD patients with low fat free mass index (FFMI) as a surrogate of muscle mass (COPDL) (FEV1 30 ± 3.6%pred, FFMI 15 ± 0.2 Kg.m−2) with patients with COPD and normal FFMI (COPDN) (FEV1 44 ± 5.8%pred, FFMI 19 ± 0.5 Kg.m−2) and a group of age and sex matched healthy controls (C) (FEV1 95 ± 3.9%pred, FFMI 20 ± 0.8 Kg.m−2) using Agilent Human Whole Genome 4x44K microarrays. The altered expression of several of these genes was confirmed by real time TaqMan PCR. Protein levels of P21 were assessed by immunoblotting.
A subset of 42 genes was differentially expressed in COPDL in comparison to both COPDN and C (PFP < 0.05; −1.5 ≥ FC ≥ 1.5). The altered expression of several of these genes was confirmed by real time TaqMan PCR and correlated with different functional and structural muscle parameters. Five of these genes (CDKN1A, GADD45A, PMP22, BEX2, CGREF1, CYR61), were associated with cell cycle arrest and growth regulation and had been previously identified in studies relating muscle wasting and ageing. Protein levels of CDKN1A, a recognized marker of premature ageing/cell cycle arrest, were also found to be increased in COPDL.
This study provides evidence of differentially expressed genes in peripheral muscle in COPD patients corresponding to relevant biological processes associated with skeletal muscle wasting and provides potential targets for future therapeutic interventions to prevent loss of muscle function and mass in COPD.
Electronic supplementary material
The online version of this article (doi:10.1186/s12931-014-0139-5) contains supplementary material, which is available to authorized users.
COPD; Skeletal Muscle Dysfunction; Skeletal muscle wasting; Gene expression; Ageing
Systemic inflammation may contribute to cachexia in patients with chronic obstructive pulmonary disease (COPD). In this longitudinal study we assessed the association between circulating C-reactive protein (CRP), tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 levels and subsequent loss of fat free mass and fat mass in more than 400 COPD patients over three years.
The patients, aged 40–76, GOLD stage II-IV, were enrolled in 2006/07, and followed annually. Fat free mass and fat mass indexes (FFMI & FMI) were calculated using bioelectrical impedance, and CRP, TNF-α, IL-1ß, and IL-6 were measured using enzyme immunoassays. Associations with mean change in FFMI and FMI of the four inflammatory plasma markers, sex, age, smoking, FEV1, inhaled steroids, arterial hypoxemia, and Charlson comorbidity score were analyzed with linear mixed models.
At baseline, only CRP was significantly (but weakly) associated with FFMI (r = 0.18, p < 0.01) and FMI (r = 0.27, p < 0.01). Univariately, higher age, lower FEV1, and use of beta2-agonists were the only significant predictors of decline in FFMI, whereas smoking, hypoxemia, Charlson score, and use of inhaled steroids predicted increased loss in FMI. Multivariately, high levels of TNF-α (but not CRP, IL-1ß or IL-6) significantly predicted loss of FFMI, however only in patients with established cachexia at entry.
This study does not support the hypothesis that systemic inflammation is the cause of accelerated loss of fat free mass in COPD patients, but suggests a role for TNF-α in already cachectic COPD patients.
Inflammation; TNF-α; COPD; Cachexia
Chronic obstructive pulmonary disease (COPD) is characterized by alveolar destruction and abnormal inflammatory responses to noxious stimuli. Surfactant protein–D (SFTPD) is immunomodulatory and essential to host defense. We hypothesized that polymorphisms in SFTPD could influence the susceptibility to COPD. We genotyped six single-nucleotide polymorphisms (SNPs) in surfactant protein D in 389 patients with COPD in the National Emphysema Treatment Trial (NETT) and 472 smoking control subjects from the Normative Aging Study (NAS). Case-control association analysis was performed using Cochran–Armitage trend tests and multivariate logistic regression. The replication of significant associations was attempted in the Boston Early-Onset COPD Study, the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Study, and the Bergen Cohort. We also correlated SFTPD genotypes with serum concentrations of surfactant protein–D (SP-D) in the ECLIPSE Study. In the NETT–NAS case-control analysis, four SFTPD SNPs were associated with susceptibility to COPD: rs2245121 (P = 0.01), rs911887 (P = 0.006), rs6413520 (P = 0.004), and rs721917 (P = 0.006). In the family-based analysis of the Boston Early-Onset COPD Study, rs911887 was associated with prebronchodilator and postbronchodilator FEV1 (P = 0.003 and P = 0.02, respectively). An intronic SNP in SFTPD, rs7078012, was associated with COPD in the ECLIPSE Study and the Bergen Cohort. Multiple SFTPD SNPs were associated with serum SP-D concentrations in the ECLIPSE Study. We demonstrated an association of polymorphisms in SFTPD with COPD in multiple populations. We demonstrated a correlation between SFTPD SNPs and SP-D protein concentrations. The SNPs associated with COPD and SP-D concentrations differed, suggesting distinct genetic influences on susceptibility to COPD and SP-D concentrations.
COPD; surfactant protein–D; single-nucleotide polymorphisms; genetics
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.
COPD; wasting; pectoral muscle area; imaging
Chronic obstructive pulmonary disease (COPD) is characterized by expiratory flow limitation, causing air trapping and lung hyperinflation. Hyperinflation leads to reduced exercise tolerance and poor quality of life in COPD patients. Total lung capacity (TLC) is an indicator of hyperinflation particularly in subjects with moderate-to-severe airflow obstruction. The aim of our study was to identify genetic variants associated with TLC in COPD.
We performed genome-wide association studies (GWASs) in white subjects from three cohorts: the COPDGene Study; the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); and GenKOLS (Bergen, Norway). All subjects were current or ex-smokers with at least moderate airflow obstruction, defined by a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) <0.7 and FEV1 < 80% predicted on post-bronchodilator spirometry. TLC was calculated by using volumetric computed tomography scans at full inspiration (TLCCT). Genotyping in each cohort was completed, with statistical imputation of additional markers. To find genetic variants associated with TLCCT, linear regression models were used, with adjustment for age, sex, pack-years of smoking, height, and principal components for genetic ancestry. Results were summarized using fixed-effect meta-analysis.
Analysis of a total of 4,543 COPD subjects identified one genome-wide significant locus on chromosome 5p15.2 (rs114929486, β = 0.42L, P = 4.66 × 10−8).
In COPD, TLCCT was associated with a SNP in dynein, axonemal, heavy chain 5 (DNAH5), a gene in which genetic variants can cause primary ciliary dyskinesia. DNAH5 could have an effect on hyperinflation in COPD.
Electronic supplementary material
The online version of this article (doi:10.1186/s12931-014-0097-y) contains supplementary material, which is available to authorized users.
Pulmonary disease; Chronic obstructive; Hyperinflation; Genome-wide association analysis; Total lung capacity; DNAH5
Elderly patients with chronic obstructive pulmonary disease (COPD) usually have a compromised nutritional status which is an independent predictor of morbidity and mortality. To know the Resting Energy Expenditure (REE) and the substrate oxidation measurement is essential to prevent these complications. This study aimed to compare the REE, respiratory quotient (RQ) and body composition between patients with and without COPD.
This case–control study assessed 20 patients with chronic obstructive pulmonary disease attending a pulmonary rehabilitation program. The group of subjects without COPD (control group) consisted of 20 elderly patients attending a university gym, patients of a private service and a public healthy care. Consumption of oxygen (O2) and carbon dioxide (CO2) was determined by indirect calorimetry and used for calculating the resting energy expenditure and respiratory quotient. Body mass index (BMI) and waist circumference (WC) were also measured. Percentage of body fat (%BF), lean mass (kg) and muscle mass (kg) were determined by bioimpedance. The fat free mass index (FFMI) and muscle mass index (MMI) were then calculated.
The COPD group had lower BMI than control (p = 0.02). However, WC, % BF, FFMI and MM-I did not differ between the groups. The COPD group had greater RQ (p = 0.01), REE (p = 0.009) and carbohydrate oxidation (p = 0.002).
Elderly patients with COPD had higher REE, RQ and carbohydrate oxidation than controls.
Chronic obstructive pulmonary disease; Resting energy expenditure; Elderly; Carbohydrate oxidation
Fat-free mass (FFM) depletion has been shown to be a better predictor of mortality than BMI in chronic obstructive pulmonary disease (COPD) patients. The specific aim of the current study was to assess the nutritional status of stable COPD patients in relation to fat free mass index profiles.
We investigated 65 male moderate-to-severe stable COPD patients. A self-reported questionnaire was applied about general characteristics and smoking history. Nutritional intake was assessed by using a 54–item quantitative food frequency questionnaire. Weight, height, mid-upper arm circumference (MUAC), waist circumference (WC), handgrip strength and body composition measurements were taken by a trained dietitian. The data were analyzed with SPSS 15.0 software.
The mean age of the patients was 62.1 ± 8.9 years. Among all of the patients 13.8% was underweight (BMI < 21 kg/m2) and 18.5% had a low fat-free mass index (FFMI < 16 kg/m2). The percentages of the patients who did not meet the daily recommended intakes (RNI) were highest for magnesium (93.8%) and calcium (92.3%). Mean daily consumptions of milk-yogurt, red meat and fruits were significantly low in the low FFMI group compared to normal FFMI group (for all; p < 0.05). Patients with normal FFMI had significantly higher weight, height, WC, MUAC, handgrip strength, fat and fat-free mass than the patients with low FFMI (for all; p < 0.05).
Dieticians should be aware of COPD patients with low FFMI in order to evaluate the nutritional intake and therefore plan nutritional strategies to improve prognosis of the disease.
COPD; Nutritional status; Dietary intake; Body composition; Fat-free mass
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
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
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.
COPD exacerbations; nicotine addiction; high-resolution CT; genetic association analysis; emphysema
Being overweight or obese is associated with a higher rate of survival in patients with advanced chronic obstructive pulmonary disease (COPD). This paradoxical relationship indicates that the influence of nutritional status on functional parameters should be further investigated.
To investigate the impact of nutritional status on body composition, exercise capacity and respiratory muscle strength in severe chronic obstructive pulmonary disease patients.
Thirty-two patients (nine women) were divided into three groups according to their body mass indices (BMI): overweight/obese (25 ≤ BMI ≤ 34.9 kg/m2, n=8), normal weight (18.5 ≤ BMI ≤ 24.9 kg/m2, n=17) and underweight (BMI <18.5 kg/m2, n=7). Spirometry, bioelectrical impedance, a six-minute walking distance test and maximal inspiratory and expiratory pressures were assessed.
Airway obstruction was similar among the groups (p=0.30); however, overweight/obese patients had a higher fat-free mass (FFM) index [FFMI=FFM/body weight2 (mean±SEM: 17±0.3 vs. 15±0.3 vs. 14±0.5 m/kg2, p<0.01)], exercise capacity (90±8 vs. 79±6 vs. 57±8 m, p=0.02) and maximal inspiratory pressure (63±7 vs. 57±5 vs. 35±8 % predicted, p=0.03) in comparison to normal weight and underweight patients, respectively. In addition, on backward multiple regression analysis, FFMI was the unique independent predictor of exercise capacity (partial r=0.52, p<0.01).
Severe chronic obstructive pulmonary disease (COPD) patients who were overweight or obese had a greater FFM, exercise capacity and inspiratory muscle strength than patients with the same degree of airflow obstruction who were of normal weight or underweight, and higher FFM was independently associated with higher exercise capacity. These characteristics of overweight or obese patients might counteract the drawbacks of excess weight and lead to an improved prognosis in COPD.
Chronic obstructive pulmonary disease; Body mass index; Body composition; fitness; Respiratory muscle strength
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.
Weight loss and depletion of fat-free mass are common problems in patients with chronic obstructive pulmonary disease (COPD) and are related to muscular weakness and exercise intolerance. Physical training of COPD patients has good effect on exercise tolerance and quality of life. The aim of this study was to examine factors that affect change in fat-free mass after physical training, in patients with COPD.
Patients were examined before and after a 4-month exercise period. Weight and height were measured, and bioelectrical impedance was performed. Fat-free mass (FFM) was calculated, by a three-compartment model, and fat-free mass index (FFMI) was calculated as FFM kg/m2 and body mass index (BMI) as kg/m2. A symptom-limited ramp ergometer test and 12-minute walk test (12MWT) were performed. Dyspnoea score of daily activities was determined by Chronic Respiratory Disease Questionnaire (CRDQ). Blood was taken for analyses of C-reactive protein (CRP) and fibrinogen. Patients with a BMI <21 kg/m2 were given nutritional support during the training period.
A total of 27 patients completed the training (64 years, FEV1 31% of predicted). Patients with low FFMI gained 1.2 kg, whereas those with normal FFMI lost 0.7 kg (p = 0.04). In multivariate analyses high age (p = 0.03), low FEV1 (p = 0.02), and a high level of dyspnoea (p = 0.01) at baseline were found to be negative predictors for increase in FFM.
Difficulties in increasing the fat-free mass in COPD patients by physical training seem to be associated with dyspnoea in daily life and impaired lung function (FEV1).
Chronic obstructive pulmonary disease; dyspnoea; exercise training; fat-free mass; nutrition
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.
ClinicalTrials.gov 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.
Pulmonary disease; Chronic obstructive; Chronic bronchitis; Genome-wide association study
Chronic obstructive pulmonary disease (COPD) is a systemic disease that leads to weight loss and muscle dysfunction resulting in an increase in mortality. This study aimed to determine the prevalence rate of malnutrition and nutritional status and also factors associated with nutritional status. A total of 149 subjects were involved in the cross-sectional study. The study was conducted at two medical centers in Kuala Lumpur, Malaysia. The results of the study showed that malnutrition was more prevalent (52.4%) in the subjects with severe stages of COPD as compared to mild and moderate COPD stages (26.2%) (P < 0.05). Fat-free mass depletion as assessed using fat-free mass index (FFMI) affected 41.9% of the subjects. Plasma vitamin A, peak expiratory flow (PEF), and handgrip were the predictors for body mass index (BMI) (R2 = 0.190, P < 0.001). Plasma vitamin A and force expiratory volume in one second (FEV1) were the predictors of FFMI (R2 = 0.082, P = 0.007). BMI was the predictor of respiratory factors, that is, FEV1% predicted (R2 = 0.052, P = 0.011). It can be concluded that there is a need to identify malnourished COPD patients for an appropriate nutrition intervention.
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.
Clinicaltrials.gov identifiers: COPDGene NCT00608764, ECLIPSE NCT00292552.
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The online version of this article (doi:10.1186/1471-2466-14-164) contains supplementary material, which is available to authorized users.
Airway disease; CT scan; Diabetes mellitus; Emphysema; Spirometry
Animal studies demonstrate the importance of the E3 ubiquitin ligases, Muscle RING-Finger Protein 1 (MuRF-1) and atrogin-1, in muscle protein degradation during acute muscle atrophy. Small clinical studies suggest MuRF-1 and atrogin-1 expression in the quadriceps muscle is also increased in stable patients with Chronic Obstructive Pulmonary Disease compared to controls. However, it remains unclear whether these ligases have a role in maintaining a muscle-wasted state in COPD patients.
32 stable COPD patients (16 with a low fat-free mass index (FFMI), 16 with a normal FFMI) and 15 controls underwent lung function and quadriceps strength tests and a percutaneous quadriceps biopsy. Quadriceps MuRF-1 and atrogin-1 protein were quantified with western blotting. Quadriceps fiber cross-sectional area (CSA) and fiber proportions were determined by immunohistochemistry on muscle sections. MuRF-1 and atrogin-1 levels were compared between COPD patients with and without a low FFMI, and between patients and controls, and correlations between MuRF-1 and atrogin-1 levels and quadriceps fiber CSA in the patients were investigated.
Atrogin-1 protein levels were lower in patients than controls, but similar in patients with a low and normal FFMI. MuRF-1 levels did not differ between any groups. MuRF-1 and atrogin-1 levels were not associated with quadriceps fiber CSA or quadriceps strength in patients.
Chronic upregulation of ubiquitin ligases was not evident in the quadriceps muscle of stable COPD patients with a low muscle mass. This does not exclude the possibility of transient increases in ubiquitin ligases during acute catabolic episodes.
muscle atrophy; muscle protein breakdown; ubiquitin ligases
The objective of the present study was to determine the association between CT phenotypes—emphysema by low attenuation area and bronchitis by airway wall thickness—and body composition parameters in a large cohort of subjects with and without COPD. In 452 COPD subjects and 459 subjects without COPD, CT scans were performed to determine emphysema (%LAA), airway wall thickness (AWT-Pi10), and lung mass. Muscle wasting based on FFMI was assessed by bioelectrical impedance. In both the men and women with COPD, FFMI was negatively associated with %LAA. FMI was positively associated with AWT-Pi10 in both subjects with and without COPD. Among the subjects with muscle wasting, the percentage emphysema was high, but the predictive value was moderate. In conclusion, the present study strengthens the hypothesis that the subgroup of COPD cases with muscle wasting have emphysema. Airway wall thickness is positively associated with fat mass index in both subjects with and without COPD.
Although most cases of chronic obstructive pulmonary disease (COPD) occur in smokers, only a fraction of smokers develop the disease. We hypothesized distinct molecular signatures for COPD and emphysema in the peripheral blood mononuclear cells (PBMCs) of current and former smokers. To test this hypothesis, we identified and validated PBMC gene expression profiles in smokers with and without COPD. We generated expression data on 136 subjects from the COPDGene study, using Affymetrix U133 2.0 microarrays (Affymetrix, Santa Clara, CA). Multiple linear regression with adjustment for covariates (gender, age, body mass index, family history, smoking status, and pack-years) was used to identify candidate genes, and ingenuity pathway analysis was used to identify candidate pathways. Candidate genes were validated in 149 subjects according to multiplex quantitative real-time polymerase chain reaction, which included 75 subjects not previously profiled. Pathways that were differentially expressed in subjects with COPD and emphysema included those that play a role in the immune system, inflammatory responses, and sphingolipid (ceramide) metabolism. Twenty-six of the 46 candidate genes (e.g., FOXP1, TCF7, and ASAH1) were validated in the independent cohort. Plasma metabolomics was used to identify a novel glycoceramide (galabiosylceramide) as a biomarker of emphysema, supporting the genomic association between acid ceramidase (ASAH1) and emphysema. COPD is a systemic disease whose gene expression signatures in PBMCs could serve as novel diagnostic or therapeutic targets.
airflow obstruction; chronic; microarray analysis; leukocytes; mononuclear
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.
COPD; Biomarkers; RAGE; ICAM1; CCL20; Emphysema
Nutritional depletion is an important manifestation of chronic obstructive pulmonary disease (COPD), which has been related to systemic inflammation. It remains unclear to what degree airway inflammation contributes to the presence or progression of nutritional depletion.
To determine whether airway inflammation and lung bacterial colonization are related to nutritional status or predict progressive weight loss and muscle atrophy in patients with COPD.
Body composition using dual energy X-ray absorptiometry, indices of airway inflammation, and bacterial colonization were measured in 234 COPD patients. Systemic inflammation was assessed from serum C reactive protein (CRP) and circulating total and differential leukocyte counts. Nutritional depletion was defined as a body mass index (BMI) less than 21 kg/m2 and/or fat-free mass index (FFMI) less than 15 or 17 kg/m2 in women and men, respectively. FFMI was calculated as the fat-free mass (FFM) corrected for body surface area. Measurements were repeated in 94 patients after a median 16-month follow-up. Regression analysis was used to assess the relationships of weight change and FFM change with indices of bacterial colonization and airway and systemic inflammation.
Nutritional depletion occurred in 37% of patients. Lung function was worsened in patients with nutritional depletion compared to those without (forced expiratory volume in 1 second 1.17 L versus 1.41 L, mean difference 0.24, 95% confidence interval 0.10 to 0.38, P<0.01). There were no differences in airway inflammation and bacterial colonization in patients with and without nutritional depletion. At baseline, BMI correlated positively with serum CRP (rs=0.14, P=0.04). Change in weight and change in FFM over time could not be predicted from baseline patient characteristics.
Nutritional depletion and progressive muscle atrophy are not related to airway inflammation or bacterial colonization. Overspill of pulmonary inflammation is not a key driver of muscle atrophy in COPD.
muscle atrophy; fat-free mass; dual-energy X-ray absorptiometry (DEXA); airway inflammation; bacteria