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Am J Respir Crit Care Med. 2019 Sep 15;200(6):721-731. doi: 10.1164/rccm.201812-2355OC.

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

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Department of Medicine, Columbia University College of Physicians & Surgeons, New York, New York.
Division of Pulmonary, Critical Care, Allergy, and Immunologic Medicine, Department of Medicine, Wake Forest University, Winston-Salem, North Carolina.
Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia.
Department of Radiology.
Department of Medicine, and.
Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa.
LA Biomed.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, California.
Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medical College, New York, New York.
Division of Respiratory, Critical Care, and Occupational Pulmonary Medicine, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah.
Division of Pulmonary and Critical Care Medicine, Michigan Medicine, Ann Arbor, Michigan.
Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, California.
Division of Pulmonary, Allergy, and Critical Care, University of Alabama at Birmingham, Birmingham, Alabama.
Department of Thoracic Medicine, Temple University, Philadelphia, Pennsylvania.
Division of Pulmonary and Critical Care, University of Illinois, Chicago, Illinois.
Division of Pulmonary and Critical Care, National Jewish, Denver, Colorado; and.
Department of Medicine, University of Arizona, Tucson, Arizona.


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.


airway remodeling; emphysema; spirometry

[Available on 2020-09-15]
[Indexed for MEDLINE]

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