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      Epidemiology, genetics, and subtyping of preserved ratio impaired spirometry (PRISm) in COPDGene

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          Abstract

          Background

          Preserved Ratio Impaired Spirometry (PRISm), defined as a reduced FEV 1 in the setting of a preserved FEV 1/FVC ratio, is highly prevalent and is associated with increased respiratory symptoms, systemic inflammation, and mortality. Studies investigating quantitative chest tomographic features, genetic associations, and subtypes in PRISm subjects have not been reported.

          Methods

          Data from current and former smokers enrolled in COPDGene (n = 10,192), an observational, cross-sectional study which recruited subjects aged 45–80 with ≥10 pack years of smoking, were analyzed. To identify epidemiological and radiographic predictors of PRISm, we performed univariate and multivariate analyses comparing PRISm subjects both to control subjects with normal spirometry and to subjects with COPD. To investigate common genetic predictors of PRISm, we performed a genome-wide association study (GWAS). To explore potential subgroups within PRISm, we performed unsupervised k-means clustering.

          Results

          The prevalence of PRISm in COPDGene is 12.3%. Increased dyspnea, reduced 6-minute walk distance, increased percent emphysema and decreased total lung capacity, as well as increased segmental bronchial wall area percentage were significant predictors (p-value <0.05) of PRISm status when compared to control subjects in multivariate models. Although no common genetic variants were identified on GWAS testing, a significant association with Klinefelter’s syndrome (47XXY) was observed (p-value < 0.001). Subgroups identified through k-means clustering include a putative “COPD-subtype”, “Restrictive-subtype”, and a highly symptomatic “Metabolic-subtype”.

          Conclusions

          PRISm subjects are clinically and genetically heterogeneous. Future investigations into the pathophysiological mechanisms behind and potential treatment options for subgroups within PRISm are warranted.

          Trial registration

          Clinicaltrials.gov Identifier: NCT000608764.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12931-014-0089-y) contains supplementary material, which is available to authorized users.

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          Most cited references27

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          Lung function and mortality in the United States: data from the First National Health and Nutrition Examination Survey follow up study.

          D Mannino (2003)
          A study was undertaken to define the risk of death among a national cohort of US adults both with and without lung disease. Participants in the first National Health and Nutrition Examination Survey (NHANES I) followed for up to 22 years were studied. Subjects were classified using a modification of the Global Initiative for Chronic Obstructive Lung Disease criteria for chronic obstructive pulmonary disease (COPD) into the following mutually exclusive categories using the forced expiratory volume in 1 second (FEV(1)), forced vital capacity (FVC), FEV(1)/FVC ratio, and the presence of respiratory symptoms: severe COPD, moderate COPD, mild COPD, respiratory symptoms only, restrictive lung disease, and no lung disease. Proportional hazard models were developed that controlled for age, race, sex, education, smoking status, pack years of smoking, years since quitting smoking, and body mass index. A total of 1301 deaths occurred in the 5542 adults in the cohort. In the adjusted proportional hazards model the presence of severe or moderate COPD was associated with a higher risk of death (hazard ratios (HR) 2.7 and 1.6, 95% confidence intervals (CI) 2.1 to 3.5 and 1.4 to 2.0), as was restrictive lung disease (HR 1.7, 95% CI 1.4 to 2.0). The presence of both obstructive and restrictive lung disease is a significant predictor of earlier death in long term follow up.
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            Global Initiative on Obstructive Lung Disease (GOLD) classification of lung disease and mortality: findings from the Atherosclerosis Risk in Communities (ARIC) study.

            To determine whether a modified Global Initiative on Obstructive Lung Diseases (GOLD) classification of chronic obstructive pulmonary disease (COPD) predicts mortality in a cohort of subjects followed for up to 11 years. We analyzed data from 15,759 adult participants, aged 43-66 years at baseline, in the Atherosclerosis Risk in Communities (ARIC) study. All baseline and follow-up data were available for 15,440 (97.9%) of the initial participants. We classified subjects using a modification of the GOLD criteria for COPD (prebronchodilator forced expiratory volume in 1s (FEV(1)) stratification of disease severity), and added a "restricted" category (FEV(1)/FVC>70% and FVC<80% predicted). We used Cox proportional hazard models to determine the risk of impaired lung function on subsequent mortality, after adjusting for age, race, sex and smoking status. 1242 (8.0%) subjects died by the end of 1997. The overall rate of death was 8.9 per 1000 person years, but varied from 5.4/1000 among normal subjects to 42.9/1000 among subjects with GOLD Stage 3 or 4 COPD. After adjusting for covariates, all GOLD categories, along with the restricted category, predicted a higher risk of death: GOLD Stage 3 or 4, hazard ratio (HR) 5.7, 95% confidence interval (CI) 4.4, 7.3; GOLD Stage 2 HR 2.4, 95% CI 2.0, 2.9; GOLD Stage 1 HR 1.4, 95% CI 1.1, 1.6; GOLD Stage 0 HR 1.5, 95% CI 1.3, 1.8; and restricted HR 2.3, 95% CI 1.9, 2.8. The modified GOLD classification system of COPD predicts mortality in this cohort of middle-aged Americans followed for up to 11 years.
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              Obstructive and restrictive lung disease and markers of inflammation: data from the Third National Health and Nutrition Examination.

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                Author and article information

                Contributors
                emily.wan@channing.harvard.edu
                repjc@channing.harvard.edu
                remhc@channing.harvard.edu
                john.hokanson@ucdenver.edu
                regane@njhealth.org
                makeb@njhealth.org
                tbeaty@jhsph.edu
                mrking@med.umich.edu
                jlcurtis@med.umich.edu
                everettd@njhealth.org
                lynchd@njhealth.org
                redld@channing.harvard.edu
                crapoj@njhealth.org
                ed.silverman@channing.harvard.edu
                Journal
                Respir Res
                Respiratory Research
                BioMed Central (London )
                1465-9921
                1465-993X
                6 August 2014
                6 August 2014
                2014
                : 15
                : 1
                : 89
                Affiliations
                [ ]Channing Division of Network Medicine, Brigham and Women’s Hospital, 181 Longwood Avenue, 4th floor, Boston, MA 2115 USA
                [ ]Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA USA
                [ ]Department of Epidemiology, Colorado School of Public Health, University of Colorado, Denver, CO USA
                [ ]National Jewish Health, Denver, CO USA
                [ ]Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD USA
                [ ]Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, MI USA
                [ ]Pulmonary and Critical Care Section, Ann Arbor Veterans Affairs Healthcare System, Ann Arbor, MI USA
                [ ]Division of Biostatistics and Bioinformatics, National Jewish Health, Denver, CO USA
                [ ]Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Denver, Denver, CO USA
                Article
                89
                10.1186/s12931-014-0089-y
                4256936
                25096860
                6eb33706-01af-496d-af15-55c5de718fef
                © Wan et al.; licensee BioMed Central Ltd. 2014

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 20 February 2014
                : 27 July 2014
                Categories
                Research
                Custom metadata
                © The Author(s) 2014

                Respiratory medicine
                spirometry,restriction,lung diseases,smoking
                Respiratory medicine
                spirometry, restriction, lung diseases, smoking

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