Dataset Information

A Genetic Risk Score Associated with Chronic Obstructive Pulmonary Disease Susceptibility and Lung Structure on Computed Tomography.

ABSTRACT: Rationale: Chronic obstructive pulmonary disease (COPD) has been associated with numerous genetic variants, yet the extent to which its genetic risk is mediated by variation in lung structure remains unknown.Objectives: To characterize associations between a genetic risk score (GRS) associated with COPD susceptibility and lung structure on computed tomography (CT).Methods: We analyzed data from MESA Lung (Multi-Ethnic Study of Atherosclerosis Lung Study), a U.S. general population-based cohort, and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study). A weighted GRS was calculated from 83 SNPs that were previously associated with lung function. Lung density, spatially matched airway dimensions, and airway counts were assessed on full-lung CT. Generalized linear models were adjusted for age, age squared, sex, height, principal components of genetic ancestry, smoking status, pack-years, CT model, milliamperes, and total lung volume.Measurements and Main Results: MESA Lung and SPIROMICS contributed 2,517 and 2,339 participants, respectively. Higher GRS was associated with lower lung function and increased COPD risk, as well as lower lung density, smaller airway lumens, and fewer small airways, without effect modification by smoking. Adjustment for CT lung structure, particularly small airway measures, attenuated associations between the GRS and FEV₁/FVC by 100% and 60% in MESA and SPIROMICS, respectively. Lung structure (P < 0.0001), but not the GRS (P > 0.10), improved discrimination of moderate-to-severe COPD cases relative to clinical factors alone.Conclusions: A GRS associated with COPD susceptibility was associated with CT lung structure. Lung structure may be an important mediator of heritability and determinant of personalized COPD risk.

SUBMITTER: Oelsner EC

PROVIDER: S-EPMC6775892 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A Genetic Risk Score Associated with Chronic Obstructive Pulmonary Disease Susceptibility and Lung Structure on Computed Tomography.

Oelsner Elizabeth C EC Ortega Victor E VE Smith Benjamin M BM Nguyen Jennifer N JN Manichaikul Ani W AW Hoffman Eric A EA Guo Xiuqing X Taylor Kent D KD Woodruff Prescott G PG Couper David J DJ Hansel Nadia N NN Martinez Fernando J FJ Paine Robert R Han Meilan K MK Cooper Christopher C Dransfield Mark T MT Criner Gerard G Krishnan Jerry A JA Bowler Russell R Bleecker Eugene R ER Peters Stephen S Rich Stephen S SS Meyers Deborah A DA Rotter Jerome I JI Barr R Graham RG

American journal of respiratory and critical care medicine 20190901 6

Rationale: Chronic obstructive pulmonary disease (COPD) has been associated with numerous genetic variants, yet the extent to which its genetic risk is mediated by variation in lung structure remains unknown.Objectives: To characterize associations between a genetic risk score (GRS) associated with COPD susceptibility and lung structure on computed tomography (CT).Methods: We analyzed data from MESA Lung (Multi-Ethnic Study of Atherosclerosis Lung Study), a U.S. general popu ...[more]

PMID: 30925230

Similar Datasets

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:BackgroundThe fractal dimension characterizing the cumulative size distribution of low attenuation area (LAA) clusters, identified with a fixed threshold such as - 950 Hounsfield Units (HU), on computed tomography (CT) sensitively detects parenchymal destruction in chronic obstructive pulmonary disease (COPD) even when the percent LAA (LAA%), a standard emphysema index, is unchanged. This study examines whether the cumulative size distribution of LAA clusters, defined with thresholds of the 15th, 25th, and 35th percentiles of a CT density histogram instead of the fixed-threshold of - 950 HU, exhibits a fractal property and whether its fractal dimension (D'15, D'25, and D'35, respectively) provides additional structural information in emphysematous lungs that is difficult to detect with the conventional - 950-HU-based fractal dimension (D950).MethodsChest inspiratory CT scans and pulmonary functions were cross-sectionally examined in 170 COPD subjects. A proxy for the inspiration level at CT scan was obtained by dividing CT-measured total lung volume (CT-TLV) by physiologically measured total lung capacity. Moreover, long-term (> 5 years) changes in D950 and the new fractal dimensions were longitudinally evaluated in 17 current and 42 former smokers with COPD.ResultsD950, but not D'15, D'25, or D'35 was weakly correlated with the proxy for the inspiration. D950, D'25, and D'35 but not D'15 correlated with LAA% and diffusion capacity. In the long-term longitudinal study, LAA% was increased and D950 and D'35 were decreased in both current and former smokers, while D'25 was decreased only in current smokers and D'15 was not changed in either group. The longitudinal changes in D'25 but not those in LAA%, D950, D'15, and D'35 were greater in current smokers than in former smokers. This greater change in D'25 in current smokers was confirmed after adjusting the change in CT-TLV and the baseline D'25.ConclusionsD'25 reflects diffusion capacity in emphysematous lungs and is robust against inspiration levels during CT scans. This new fractal dimension might provide additional structural information that is difficult to detect with the conventional D950 and LAA% and allow for more sensitive evaluation of emphysema progression over time.

Dataset Information

A Genetic Risk Score Associated with Chronic Obstructive Pulmonary Disease Susceptibility and Lung Structure on Computed Tomography.

Publications

A Genetic Risk Score Associated with Chronic Obstructive Pulmonary Disease Susceptibility and Lung Structure on Computed Tomography.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets