Dataset Information

Identifying a Deletion Affecting Total Lung Capacity Among Subjects in the COPDGene Study Cohort.

ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a progressive disease with both environmental and genetic risk factors. Genome-wide association studies (GWAS) have identified multiple genomic regions influencing risk of COPD. To thoroughly investigate the genetic etiology of COPD, however, it is also important to explore the role of copy number variants (CNVs) because the presence of structural variants can alter gene expression and can be causal for some diseases. Here, we investigated effects of polymorphic CNVs on quantitative measures of pulmonary function and chest computed tomography (CT) phenotypes among subjects enrolled in COPDGene, a multisite study. COPDGene subjects consist of roughly one-third African American (AA) and two-thirds non-Hispanic white adult smokers (with or without COPD). We estimated CNVs using PennCNV on 9,076 COPDGene subjects using Illumina's Omni-Express genome-wide marker array. We tested for association between polymorphic CNV components (defined as disjoint intervals of copy number regions) for several quantitative phenotypes associated with COPD within each racial group. Among the AAs, we identified a polymorphic CNV on chromosome 5q35.2 located between two genes (FAM153B and SIMK1, but also harboring several pseudo-genes) giving genome-wide significance in tests of association with total lung capacity (TLCCT ) as measured by chest CT scans. This is the first study of genome-wide association tests of polymorphic CNVs and TLCCT . Although the ARIC cohort did not have the phenotype of TLCCT , we found similar counts of CNV deletions and amplifications among AA and European subjects in this second cohort.

SUBMITTER: Begum F

PROVIDER: S-EPMC4679532 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Identifying a Deletion Affecting Total Lung Capacity Among Subjects in the COPDGene Study Cohort.

Begum Ferdouse F Ruczinski Ingo I Li Shengchao S Silverman Edwin K EK Cho Michael H MH Lynch David A DA Curran-Everett Douglas D Crapo James J Scharpf Robert B RB Parker Margaret M MM Hetmanski Jacqueline B JB Beaty Terri H TH

Genetic epidemiology 20151207 1

Chronic obstructive pulmonary disease (COPD) is a progressive disease with both environmental and genetic risk factors. Genome-wide association studies (GWAS) have identified multiple genomic regions influencing risk of COPD. To thoroughly investigate the genetic etiology of COPD, however, it is also important to explore the role of copy number variants (CNVs) because the presence of structural variants can alter gene expression and can be causal for some diseases. Here, we investigated effects ...[more]

PMID: 26643968

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Project description:The coexistence of gastroesophageal reflux disease (GERD) and COPD has been recognized, but there has been no comprehensive evaluation of the impact of GERD on COPD-related health status and patient-centered outcomes.Cross-sectional and longitudinal study of 4,483 participants in the COPDGene cohort who met GOLD criteria for COPD. Physician-diagnosed GERD was ascertained by questionnaire. Clinical features, spirometry and imaging were compared between COPD subjects without versus with GERD. We evaluated the relationship between GERD and symptoms, exacerbations and markers of microaspiration in univariate and multivariate models. Associations were additionally tested for the confounding effect of covariates associated with a diagnosis of GERD and the use of proton-pump inhibitor medications (PPIs). To determine whether GERD is simply a marker for the presence of other conditions independently associated with worse COPD outcomes, we also tested models incorporating a GERD propensity score.GERD was reported by 29% of subjects with female predominance. Subjects with GERD were more likely to have chronic bronchitis symptoms, higher prevalence of prior cardiovascular events (combined myocardial infarction, coronary artery disease and stroke 21.3% vs. 13.4.0%, p?<?0.0001). Subjects with GERD also had more severe dyspnea (MMRC score 2.2 vs. 1.8, p?<?0.0001), and poorer quality of life (QOL) scores (St. George's Respiratory Questionnaire (SGRQ) total score 41.8 vs. 34.9, p?<?0.0001; SF36 Physical Component Score 38.2 vs. 41.4, p?<?0.0001). In multivariate models, a significant relationship was detected between GERD and SGRQ (3.4 points difference, p?<?0.001) and frequent exacerbations at baseline (?2 exacerbation per annum at inclusion OR 1.40, p?=?0.006). During a mean follow-up time of two years, GERD was also associated with frequent (?2/year exacerbations OR 1.40, p?=?0.006), even in models in which PPIs, GERD-PPI interactions and a GERD propensity score were included. PPI use was associated with frequent exacerbator phenotype, but did not meaningfully influence the GERD-exacerbation association.In COPD the presence of physician-diagnosed GERD is associated with increased symptoms, poorer QOL and increased frequency of exacerbations at baseline and during follow-up. These associations are maintained after controlling for PPI use. The PPI-exacerbations association could result from confounding-by-indication.

Project description:The 2011 GOLD (Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease [COPD]) consensus report uses symptoms, exacerbation history, and forced expiratory volume (FEV1)% to categorise patients according to disease severity and guide treatment. We aimed to assess both the influence of symptom instrument choice on patient category assignment and prospective exacerbation risk by category.Patients were recruited from 21 centres in the USA, as part of the COPDGene study. Eligible patients were aged 45-80 years, had smoked for 10 pack-years or more, and had an FEV1/forced vital capacity (FVC) <0·7. Categories were defined with the modified Medical Research Council (mMRC) dyspnoea scale (score 0-1 vs ?2) and the St George's Respiratory Questionnaire (SGRQ; ?25 vs <25 as a surrogate for the COPD Assessment Test [CAT] ?10 vs <10) in addition to COPD exacerbations in the previous year (<2 vs ? 2), and lung function (FEV1% predicted ?50 vs <50). Statistical comparisons were done with k-sample permutation tests. This study cohort is registered with ClinicalTrials.gov, number NCT00608764.4484 patients with COPD were included in this analysis. Category assignment using the mMRC scale versus SGRQ were similar but not identical. On the basis of the mMRC scale, 1507 (33·6%) patients were assigned to category A, 919 (20·5%) to category B, 355 (7·9%) to category C, and 1703 (38·0%) to category D; on the basis of the SGRQ, 1317 (29·4%) patients were assigned to category A, 1109 (24·7%) to category B, 221 (4·9%) to category C, and 1837 (41·0%) to category D (? coefficient for agreement, 0·77). Significant heterogeneity in prospective exacerbation rates (exacerbations/person-years) were seen, especially in the D subcategories, depending on the risk factor that determined category assignment (lung function only [0·89, 95% CI 0·78-1·00]), previous exacerbation history only [1·34, 1·0-1·6], or both [1·86, 1·6-2·1; p<0·0001]).The GOLD classification emphasises the importance of symptoms and exacerbation risk when assessing COPD severity. The choice of symptom measure influences category assignment. The relative number of patients with low symptoms and high risk for exacerbations (category C) is low. Differences in exacerbation rates for patients in the highest risk category D were seen depending on whether risk was based on lung function, exacerbation history, or both.National Heart, Lung, and Blood Institute, and the COPD Foundation through contributions from AstraZeneca, Boehringer Ingelheim, Novartis, and Sepracor.

Project description:RationaleGastroesophageal reflux disease (GERD) is a common comorbidity in chronic obstructive pulmonary disease (COPD) and has been associated with increased risk of acute exacerbations, hospitalization, emergency room visits, costs, and quality-of-life impairment. However, it remains unclear whether GERD contributes to the progression of COPD as measured by lung function or computed tomography.ObjectiveTo determine the impact of GERD on longitudinal changes in lung function and radiographic lung disease in the COPDGene cohort.MethodsWe evaluated 5728 participants in the COPDGene cohort who completed Phase I (baseline) and Phase II (5-year follow-up) visits. GERD status was based on participant-reported physician diagnoses. We evaluated associations between GERD and annualized changes in lung function [forced expired volume in 1 s (FEV1) and forced vital capacity (FVC)] and quantitative computed tomography (QCT) metrics of airway disease and emphysema using multivariable regression models. These associations were further evaluated in the setting of GERD treatment with proton-pump inhibitors (PPI) and/or histamine-receptor 2 blockers (H2 blockers).ResultsGERD was reported by 2101 (36.7%) participants at either Phase I and/or Phase II. GERD was not associated with significant differences in slopes of FEV1 (difference of - 2.53 mL/year; 95% confidence interval (CI), - 5.43 to 0.37) or FVC (difference of - 3.05 mL/year; 95% CI, - 7.29 to 1.19), but the odds of rapid FEV1 decline of ≥40 mL/year was higher in those with GERD (adjusted odds ratio (OR) 1.20; 95%CI, 1.07 to 1.35). Participants with GERD had increased progression of QCT-measured air trapping (0.159%/year; 95% CI, 0.054 to 0.264), but not other QCT metrics such as airway wall area/thickness or emphysema. Among those with GERD, use of PPI and/or H2 blockers was associated with faster decline in FEV1 (difference of - 6.61 mL/year; 95% CI, - 11.9 to - 1.36) and FVC (difference of - 9.26 mL/year; 95% CI, - 17.2 to - 1.28).ConclusionsGERD was associated with faster COPD disease progression as measured by rapid FEV1 decline and QCT-measured air trapping, but not by slopes of lung function. The magnitude of the differences was clinically small, but given the high prevalence of GERD, further investigation is warranted to understand the potential disease-modifying role of GERD in COPD pathogenesis and progression.Clinical trials registrationNCT00608764 .

Dataset Information

Identifying a Deletion Affecting Total Lung Capacity Among Subjects in the COPDGene Study Cohort.

Publications

Identifying a Deletion Affecting Total Lung Capacity Among Subjects in the COPDGene Study Cohort.

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