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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 721-731 |
| Number of pages | 11 |
| Journal | American journal of respiratory and critical care medicine |
| Volume | 200 |
| Issue number | 6 |
| DOIs | |
| State | Published - Sep 15 2019 |
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Keywords
- Airway remodeling
- Emphysema
- Spirometry
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
- Critical Care and Intensive Care Medicine
Cite this
A genetic risk score associated with chronic obstructive pulmonary disease susceptibility and lung structure on computed tomography. / Oelsner, Elizabeth C.; Ortega, Victor E.; Smith, Benjamin M.; Nguyen, Jennifer N.; Manichaikul, Ani W.; Hoffman, Eric A.; Guo, Xiuqing; Taylor, Kent D.; Woodruff, Prescott G.; Couper, David J.; Hansel, Nadia; Martinez, Fernando J.; Paine, Robert; Han, Meilan K.; Cooper, Christopher; Dransfield, Mark T.; Criner, Gerard; Krishnan, Jerry A.; Bowler, Russell; Bleecker, Eugene R.; Peters, Stephen; Rich, Stephen S.; Meyers, Deborah A.; Rotter, Jerome I.; Graham Barr, R.
In: American journal of respiratory and critical care medicine, Vol. 200, No. 6, 15.09.2019, p. 721-731.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A genetic risk score associated with chronic obstructive pulmonary disease susceptibility and lung structure on computed tomography
AU - Oelsner, Elizabeth C.
AU - Ortega, Victor E.
AU - Smith, Benjamin M.
AU - Nguyen, Jennifer N.
AU - Manichaikul, Ani W.
AU - Hoffman, Eric A.
AU - Guo, Xiuqing
AU - Taylor, Kent D.
AU - Woodruff, Prescott G.
AU - Couper, David J.
AU - Hansel, Nadia
AU - Martinez, Fernando J.
AU - Paine, Robert
AU - Han, Meilan K.
AU - Cooper, Christopher
AU - Dransfield, Mark T.
AU - Criner, Gerard
AU - Krishnan, Jerry A.
AU - Bowler, Russell
AU - Bleecker, Eugene R.
AU - Peters, Stephen
AU - Rich, Stephen S.
AU - Meyers, Deborah A.
AU - Rotter, Jerome I.
AU - Graham Barr, R.
PY - 2019/9/15
Y1 - 2019/9/15
N2 - 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.
AB - 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.
KW - Airway remodeling
KW - Emphysema
KW - Spirometry
UR - http://www.scopus.com/inward/record.url?scp=85072176635&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85072176635&partnerID=8YFLogxK
U2 - 10.1164/rccm.201812-2355OC
DO - 10.1164/rccm.201812-2355OC
M3 - Article
C2 - 30925230
AN - SCOPUS:85072176635
VL - 200
SP - 721
EP - 731
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
SN - 1073-449X
IS - 6
ER -