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Variants of asthma and chronic obstructive pulmonary disease genes and lung function decline in aging.

ABSTRACT: A substantial proportion of the general population has low lung function, and lung function is known to decrease as we age. Low lung function is a feature of several pulmonary disorders, such as uncontrolled asthma and chronic obstructive pulmonary disease. The objective of this study is to investigate the association of polymorphisms in asthma and chronic obstructive pulmonary disease candidate genes with rates of lung function decline in a general population sample of aging men.We analyzed data from a cohort of 1,047 Caucasian men without known lung disease, who had a mean of 25 years of lung function data, and on whom DNA was available. The cohort was randomly divided into two groups, and we tested a total of 940 single-nucleotide polymorphisms in 44 asthma and chronic obstructive pulmonary disease candidate genes in the first group (testing cohort, n = 545) for association with change in forced expiratory volume in 1 second over time.One hundred nineteen single-nucleotide polymorphisms that showed nominal associations in the testing cohort were then genotyped and tested in the second group (replication cohort, n = 502). Evidence for association from the testing and replication cohorts were combined, and after adjustment for multiple testing, seven variants of three genes (DPP10, NPSR1, and ADAM33) remained significantly associated with change in forced expiratory volume in 1 second over time.Our findings that genetic variants of genes involved in asthma and chronic obstructive pulmonary disease are associated with lung function decline in normal aging participants suggest that similar genetic mechanisms may underlie lung function decline in both disease and normal aging processes.

SUBMITTER: Poon AH

PROVIDER: S-EPMC4111635 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Variants of asthma and chronic obstructive pulmonary disease genes and lung function decline in aging.

Poon Audrey H AH Houseman E Andres EA Ryan Louise L Sparrow David D Vokonas Pantel S PS Litonjua Augusto A AA

The journals of gerontology. Series A, Biological sciences and medical sciences 20131119 7

<h4>Background</h4>A substantial proportion of the general population has low lung function, and lung function is known to decrease as we age. Low lung function is a feature of several pulmonary disorders, such as uncontrolled asthma and chronic obstructive pulmonary disease. The objective of this study is to investigate the association of polymorphisms in asthma and chronic obstructive pulmonary disease candidate genes with rates of lung function decline in a general population sample of aging ...[more]

PMID: 24253534

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Project description:RationaleThe rate of decline of lung function is greater than age-related change in a substantial proportion of patients with chronic obstructive pulmonary disease, even after smoking cessation. Regions of the lung adjacent to emphysematous areas are subject to abnormal stretch during respiration, and this biomechanical stress likely influences emphysema initiation and progression.ObjectivesTo assess whether quantifying this penumbra of lung at risk would predict FEV1 decline.MethodsWe analyzed paired inspiratory-expiratory computed tomography images at baseline of 680 subjects participating in a large multicenter study (COPDGene) over approximately 5 years. By matching inspiratory and expiratory images voxel by voxel using image registration, we calculated the Jacobian determinant, a measure of local lung expansion and contraction with respiration. We measured the distance between each normal voxel to the nearest emphysematous voxel, and quantified the percentage of normal voxels within each millimeter distance from emphysematous voxels as mechanically affected lung (MAL). Multivariable regression analyses were performed to assess the relationship between the Jacobian determinant, MAL, and FEV1 decline.Measurements and main resultsThe mean (SD) rate of decline in FEV1 was 39.0 (58.6) ml/yr. There was a progressive decrease in the mean Jacobian determinant of both emphysematous and normal voxels with increasing disease stage (P < 0.001). On multivariable analyses, the mean Jacobian determinant of normal voxels within 2 mm of emphysematous voxels (MAL2) was significantly associated with FEV1 decline. In mild-moderate disease, for participants at or above the median MAL2 (threshold, 36.9%), the mean decline in FEV1 was 56.4 (68.0) ml/yr versus 43.2 (59.9) ml/yr for those below the median (P = 0.044).ConclusionsAreas of normal-appearing lung are mechanically influenced by emphysematous areas and this lung at risk is associated with lung function decline. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).

Project description:Progressive decline in lung function is a hallmark of chronic obstructive pulmonary disease (COPD). Although airway dysbiosis occurs in COPD, whether it contributes to disease progression remains unknown. Here, through a longitudinal analysis on 181 COPD individuals from two large cohorts involving four UK clinical centers, we showed that baseline airway dysbiosis, characterized by enrichment of opportunistic pathogenic taxa, was associated with rapid forced expiratory volume in one second (FEV1) decline over two years. Co-presence of Moraxella, Staphylococcus and Stenotrophomonas was associated with an accelerated FEV1 decline by 139.7 mL/year. The dysbiosis was associated with exacerbation-related FEV1 fall and sudden FEV1 fall at clinical stability, two critical events contributing to long-term FEV1 decline. The microbiota association with FEV1 decline was validated in a third, independent cohort in China. Human multi-omics, murine and cellular mechanistic studies showed that chronic airway colonization of Staphylococcus aureus promoted lung function decline through producing homocysteine, which elicited an apoptosis-to-NETosis shift in neutrophils toward persistent inflammation via AKT1-S100A8/A9 axis. Prophylactic and therapeutic depletion of S. aureus via bacteriophage restored lung function in emphysema mice. These results provide a fresh approach to slow COPD progression by targeting the airway microbiome. Linked studies:UPLC-MS/MS assays of human samples are reported in this study.UPLC-MS/MS assays of murine samples are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS6894' rel='noopener noreferrer' target='_blank'>MTBLS6894</a>.UPLC-MS/MS assays of original cohort human samples are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS4017' rel='noopener noreferrer' target='_blank'>MTBLS4017</a>.

Project description:RationaleChronic lower respiratory diseases (CLRDs), including chronic obstructive pulmonary disease (COPD) and asthma, are the fourth leading cause of death. Prior studies suggest that albuminuria, a biomarker of endothelial injury, is increased in patients with COPD.ObjectivesTo test whether albuminuria was associated with lung function decline and incident CLRDs.MethodsSix U.S. population-based cohorts were harmonized and pooled. Participants with prevalent clinical lung disease were excluded. Albuminuria (urine albumin-to-creatinine ratio) was measured in spot samples. Lung function was assessed by spirometry. Incident CLRD-related hospitalizations and deaths were classified via adjudication and/or administrative criteria. Mixed and proportional hazards models were used to test individual-level associations adjusted for age, height, weight, sex, race/ethnicity, education, birth year, cohort, smoking status, pack-years of smoking, renal function, hypertension, diabetes, and medications.Measurements and main resultsAmong 10,961 participants with preserved lung function, mean age at albuminuria measurement was 60 years, 51% were never-smokers, median albuminuria was 5.6 mg/g, and mean FEV1 decline was 31.5 ml/yr. For each SD increase in log-transformed albuminuria, there was 2.81% greater FEV1 decline (95% confidence interval [CI], 0.86-4.76%; P = 0.0047), 11.02% greater FEV1/FVC decline (95% CI, 4.43-17.62%; P = 0.0011), and 15% increased hazard of incident spirometry-defined moderate-to-severe COPD (95% CI, 2-31%, P = 0.0021). Each SD log-transformed albuminuria increased hazards of incident COPD-related hospitalization/mortality by 26% (95% CI, 18-34%, P < 0.0001) among 14,213 participants followed for events. Asthma events were not significantly associated. Associations persisted in participants without current smoking, diabetes, hypertension, or cardiovascular disease.ConclusionsAlbuminuria was associated with greater lung function decline, incident spirometry-defined COPD, and incident COPD-related events in a U.S. population-based sample.

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Variants of asthma and chronic obstructive pulmonary disease genes and lung function decline in aging.

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Variants of asthma and chronic obstructive pulmonary disease genes and lung function decline in aging.

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