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Am J Respir Crit Care Med. 2019 Mar 29. doi: 10.1164/rccm.201812-2355OC. [Epub ahead of print]

A Genetic Risk Score Associated with COPD Susceptibility and Lung Structure on Computed Tomography.

Author information

1
Columbia University, Medicine, New York, New York, United States ; eco7@cumc.columbia.edu.
2
Wake Forest School of Medicine, Center for Genomics and Personalized Medicine Research, Winston-Salem, North Carolina, United States.
3
Columbia University Medical Center, Medicine, NY, New York, United States.
4
University of Virginia, 2358, Charlottesville, Virginia, United States.
5
University of Virginia, Center for Public Health Genomics, Charlottesville, Virginia, United States.
6
University of Iowa Carver College of Medicine, Radiology, Iowa City, Iowa, United States.
7
Los Angeles Biomedical Research Institute, 117316, Translational Genomics and Population Sciences, Torrance, California, United States.
8
Harbor-UCLA Medical Center, Institute for Translational Genomics and Populations Sciences, Torrance, California, United States.
9
UCSF, Division of Pulmonary and Critical Care Medicine, Department of Medicine and CVRI, San Francisco, California, United States.
10
University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States.
11
Johns Hopkins University, Medicine, Baltimore, Maryland, United States.
12
Cornell Medical College, New York, New York, United States.
13
University of Utah, Salt Lake City, Utah, United States.
14
University of Michigan, Internal Medicine, Ann Arbor, Michigan, United States.
15
Harbor-UCLA Medical Center, Torrance, California, United States.
16
University of Alabama at Birmingham and the Birmingham VA Medical Center, Medicine/Pulmonary, Allergy and Critical Care, Birmingham, Alabama, United States.
17
Temple University Hospital, Pulm & Crit Care Medicine, Philadelphia, Pennsylvania, United States.
18
University of Illinois at Chicago, 14681, Chicago, Illinois, United States.
19
National Jewish Medical and Research Center, Department of Medicine, Denver, Colorado, United States.
20
University of Arizona Arizona Health Sciences Center, 12217, Medicine, Tucson, Arizona, United States.
21
Wake Forest School of Medicine Medical Center, Section on Pulmonary, Critical Care, Allergy & Immunological Diseases, Winston-Salem, North Carolina, United States.
22
University of Arizona Arizona Health Sciences Center, 12217, Tucson, Arizona, United States.
23
Columbia University, Epidemiology, New York, New York, United States.

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 the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study, a US general population-based cohort, and SPIROMICS, a study of COPD. A weighted GRS was calculated from 83 single nucleotide polymorphisms 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 airways measures, attenuated associations between the GRS and FEV1/FVC by 100% and 60% in MESA and SPIROMICS, respectively. Lung structure (P<.0001), but not the GRS (P>.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.

KEYWORDS:

Airway remodeling; Emphysema; Spirometry

PMID:
30925230
DOI:
10.1164/rccm.201812-2355OC

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