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 N.
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.
N1 - Funding Information:
Primarily supported by NHLBI grants K23-HL130627, K08-HL118128, R01-HL077612, R01-HL093081 and R01-HL130506. MESA (Multi-Ethnic Study of Atherosclerosis), MESA Lung, and the MESA SHARe project are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. The MESA Lung Study was supported by R01-HL077612 and R01-HL093081. Development of the MESA COPD genetic risk score was supported by NHLBI grant R01-HL131565. Funding for SHARe genotyping was provided by NHLBI contract N02-HL-64278. Genotyping was performed at Affymetrix and the Broad Institute of Harvard and MIT using the Affymetrix Genome-Wide Human SNP Array 6.0. This publication was developed under STAR research assistance agreements RD831697 (MESA Air) and RD-83830001 (MESA Air Next Stage) awarded by the U.S. Environmental Protection Agency (EPA). It has not been formally reviewed by the EPA. The views expressed in this document are solely those of the authors and the EPA does not endorse any products or commercial services mentioned in this publication. SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) was supported by contracts from the NIH and NHLBI (HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, and HHSN268200900020C), which were supplemented by contributions made through the Foundation for the NIH from AstraZeneca, Bellerophon Therapeutics, Boehringer Ingelheim Pharmaceuticals Inc., Chiesi Farmaceutici SpA, Forest Research Institute Inc., GlaxoSmithKline, Grifols Therapeutics Inc., Ikaria Inc., Nycomed GmbH, Takeda Pharmaceutical Co., Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals Inc., and Sanofi. Neither the NHLBI nor the EPA was involved in collection, analysis, or interpretation of the data; writing of this report; or the decision to submit for publication.
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
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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 -