Dataset Information

Phenotypic and genetic heterogeneity among subjects with mild airflow obstruction in COPDGene.

ABSTRACT:

Background

Chronic obstructive pulmonary disease (COPD) is characterized by marked phenotypic heterogeneity. Most previous studies have focused on COPD subjects with FEV1 < 80% predicted. We investigated the clinical and genetic heterogeneity in subjects with mild airflow limitation in spirometry grade 1 defined by the Global Initiative for chronic Obstructive Lung Disease (GOLD 1).

Methods

Data from current and former smokers participating in the COPDGene Study (NCT00608764) were analyzed. K-means clustering was performed to explore subtypes within 794 GOLD 1 subjects. For all subjects with GOLD 1 and with each cluster, a genome-wide association study and candidate gene testing were performed using smokers with normal lung function as a control group. Combinations of COPD genome-wide significant single nucleotide polymorphisms (SNPs) were tested for association with FEV1 (% predicted) in GOLD 1 and in a combined group of GOLD 1 and smoking control subjects.

Results

K-means clustering of GOLD 1 subjects identified putative "near-normal", "airway-predominant", "emphysema-predominant" and "lowest FEV1% predicted" subtypes. In non-Hispanic whites, the only SNP nominally associated with GOLD 1 status relative to smoking controls was rs7671167 (FAM13A) in logistic regression models with adjustment for age, sex, pack-years of smoking, and genetic ancestry. The emphysema-predominant GOLD 1 cluster was nominally associated with rs7671167 (FAM13A) and rs161976 (BICD1). The lowest FEV1% predicted cluster was nominally associated with rs1980057 (HHIP) and rs1051730 (CHRNA3). Combinations of COPD genome-wide significant SNPs were associated with FEV1 (% predicted) in a combined group of GOLD 1 and smoking control subjects.

Conclusions

Our results indicate that GOLD 1 subjects show substantial clinical heterogeneity, which is at least partially related to genetic heterogeneity.

SUBMITTER: Lee JH

PROVIDER: S-EPMC4253548 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Publications

Phenotypic and genetic heterogeneity among subjects with mild airflow obstruction in COPDGene.

Lee Jin Hwa JH Cho Michael H MH McDonald Merry-Lynn N ML Hersh Craig P CP Castaldi Peter J PJ Crapo James D JD Wan Emily S ES Dy Jennifer G JG Chang Yale Y Regan Elizabeth A EA Hardin Megan M DeMeo Dawn L DL Silverman Edwin K EK

Respiratory medicine 20140811 10

<h4>Background</h4>Chronic obstructive pulmonary disease (COPD) is characterized by marked phenotypic heterogeneity. Most previous studies have focused on COPD subjects with FEV1 < 80% predicted. We investigated the clinical and genetic heterogeneity in subjects with mild airflow limitation in spirometry grade 1 defined by the Global Initiative for chronic Obstructive Lung Disease (GOLD 1).<h4>Methods</h4>Data from current and former smokers participating in the COPDGene Study (NCT00608764) were ...[more]

PMID: 25154699

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Project description:BackgroundPatients with COPD need to cope with a disabling disease, which leads to health status impairment.AimTo investigate the long term change of health status in subjects with mild to moderate airflow obstruction and to compare this to subjects without airflow obstruction, with and without a smoking history. Second, to investigate the factors potentially associated to rapid health status decline in our total cohort.MethodsTwo hundred and one subjects were included. Generic [Short form 36 health survey (SF36) and EuroQol - 5 dimensions (EQ-5D)] and disease specific [Clinical COPD questionnaire (CCQ) and COPD Assessment Test (CAT)] health status questionnaires were regularly repeated over a six years period. Other functional outcomes comprised measures of lung function, physical fitness, physical activity and emotional state.ResultsOn average, health status decline did not differ between groups with the exception of the EQ-5D index, which deteriorated faster in subjects with airflow obstruction compared to the never smoking control group [- 0.018(0.008) versus 0.00006(0.003), p = 0.03]. Subjects presenting at least one exacerbation had faster rate of deterioration measured with CAT [0.91(0.21) versus - 0.26(0.25), p < 0.01]. Characteristics of the fast declining group were older age, worse lung function, physical fitness, physical activity and disease specific baseline health status. Subjects with airflow obstruction had a 2.5 (95% CI 1.36-4.71) higher risk of presenting fast overall health status decline. Fast overall decline was associated with the presence of acute exacerbation(s) (44% of the subjects with exacerbation(s) versus 17% of subjects without exacerbation, p = 0.03). Changes in fat free mass, functional exercise capacity and in symptoms of anxiety and depression correlated weakly to changes in health status measured with all questionnaires.ConclusionSubjects with mild airflow obstruction present a significant deterioration of health status, which is generally not much faster compared to smoking and never smoking controls. Subjects with fast decline in overall health status are older and more likely to have airflow obstruction, acute respiratory exacerbation(s), reduced physical fitness, physical activity and impaired COPD specific health status at baseline.Trial registrationNCT01314807 - retrospectively registered on March 2011.

Project description:BackgroundExercise capacity is an important feature in patients with COPD. Its impairment drives disability and dependency for daily activities performance. This study evaluated the six years change in exercise capacity in subjects with airflow obstruction and compared this to subjects without airflow obstruction, with and without a smoking history.MethodsCardiopulmonary exercise tests (CPET) were repeatedly performed during a six years follow up period. Peak oxygen uptake (VO2peak), work rate (WRpeak), heart rate (HRpeak), minute ventilation (VEpeak), respiratory exchange ratio (RERpeak) and ventilatory reserve (VE/MVV) were collected as effort dependent outcomes. The slopes of oxygen uptake, ventilatory and mechanical efficiency (OUES, ΔVE/ΔVCO2 and ΔVO2/ΔWR) were collected as effort independent outcomes.ResultsOne hundred and thirty-eight subjects were included. Thirty-eight presented airflow obstruction (63±6 years, 74% men, FEV1 90±15%pred), 44 had a smoking history but no airflow obstruction (61±5 years, 61% men, FEV1 105±15%pred) and 56 had never smoked (61±7 years, 57% men, FEV1 117±18%pred). At baseline, the airflow obstruction group had slightly worse exercise capacity in comparison to the never smoking control group, in absolute terms and expressed as percentage of the predicted value (VO2peak = 27±5 versus 32±8 ml/min/kg, p<0.01; 112±29 versus 130±33%pred, p = 0.04). Most exercise variables showed a statistically significant yearly deterioration, with exception of VE/MVV, ΔVE/ΔVCO2 and ΔVO2/ΔWR. The yearly decline in VO2peak and OUES was not faster in subjects with airflow obstruction than in smoking and never smoking controls (VO2peak -67 (9) versus -76 (9) ml/min, p = 0.44 and versus -58 (9), p = 0.47; OUES -32 (11) versus -68 (10), p = 0.03 and versus -68 (13), p = 0.03).ConclusionsWith exception of VO2peak, effort dependent variables deteriorated faster in subjects with airflow obstruction compared to never smoking controls. The deterioration of effort independent variables, however, was not accelerated in the airflow obstruction group compared to controls.

Project description:Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation. Spirometry loops are not smooth curves and have undulations and peaks that likely reflect heterogeneity of airflow.Objectives: To assess whether the Peak Index, the number of peaks adjusted for lung size, is associated with clinical outcomes.Methods: We analyzed spirometry data of 9,584 participants enrolled in the COPDGene study and counted the number of peaks in the descending part of the expiratory flow-volume curve from the peak expiratory flow to end-expiration. We adjusted the peaks count for the volume of the lungs from peak expiratory flow to end-expiration to derive the Peak Index. Multivariable regression analyses were performed to test associations between the Peak Index and lung function, respiratory morbidity, structural lung disease on computed tomography (CT), forced expiratory volume in 1 second (FEV1) decline, and mortality.Results: The Peak Index progressively increased from Global Initiative for Chronic Obstructive Lung Disease stage 0 through 4 (P < 0.001). On multivariable analysis, the Peak Index was significantly associated with CT emphysema (adjusted β = 0.906; 95% confidence interval [CI], 0.789 to 1.023; P < 0.001) and small airways disease (adjusted β = 1.367; 95% CI, 1.188 to 1.545; P < 0.001), St. George's Respiratory Questionnaire score (adjusted β = 1.075; 95% CI, 0.807 to 1.342; P < 0.001), 6-minute-walk distance (adjusted β = -1.993; 95% CI, -3.481 to -0.506; P < 0.001), and FEV1 change over time (adjusted β = -1.604; 95% CI, -2.691 to -0.516; P = 0.004), after adjustment for age, sex, race, body mass index, current smoking status, pack-years of smoking, and FEV1. The Peak Index was also associated with the BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index and mortality (P < 0.001).Conclusions: The Peak Index is a spirometry metric that is associated with CT measures of lung disease, respiratory morbidity, lung function decline, and mortality.Clinical trial registered with www.clinicaltrials.gov (NCT00608764).

Dataset Information

Phenotypic and genetic heterogeneity among subjects with mild airflow obstruction in COPDGene.

Background

Methods

Results

Conclusions

Publications

Phenotypic and genetic heterogeneity among subjects with mild airflow obstruction in COPDGene.

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