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

TitleA Genetic Risk Score Associated with Chronic Obstructive Pulmonary Disease Susceptibility and Lung Structure on Computed Tomography.
Publication TypePublication
Year2019
AuthorsOelsner EC, Ortega VE, Smith BM, Nguyen JN, Manichaikul AW, Hoffman EA, Guo X, Taylor KD, Woodruff PG, Couper DJ, Hansel NN, Martinez FJ, Paine R, Han MK, Cooper C, Dransfield MT, Criner G, Krishnan JA, Bowler R, Bleecker ER, Peters S, Rich SS, Meyers DA, Rotter JI, R Barr G
JournalAm J Respir Crit Care Med
Volume200
Issue6
Pagination721-731
Date Published2019 09 15
ISSN1535-4970
KeywordsAged, Female, Genetic Predisposition to Disease, Humans, Lung, Male, Middle Aged, Pulmonary Disease, Chronic Obstructive, Risk Assessment, Tomography, X-Ray Computed, United States
Abstract

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. To characterize associations between a genetic risk score (GRS) associated with COPD susceptibility and lung structure on computed tomography (CT). 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. 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 FEV/FVC by 100% and 60% in MESA and SPIROMICS, respectively. Lung structure ( < 0.0001), but not the GRS ( > 0.10), improved discrimination of moderate-to-severe COPD cases relative to clinical factors alone. 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.

DOI10.1164/rccm.201812-2355OC
Alternate JournalAm J Respir Crit Care Med
PubMed ID30925230
PubMed Central IDPMC6775892
Grant ListU24 HL141762 / HL / NHLBI NIH HHS / United States
P30 ES006694 / ES / NIEHS NIH HHS / United States
N01HC95169 / HL / NHLBI NIH HHS / United States
R01 HL077612 / HL / NHLBI NIH HHS / United States
HHSN268200900016C / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
N01HC95165 / HL / NHLBI NIH HHS / United States
HHSN268201500003I / HL / NHLBI NIH HHS / United States
HHSN268201500003C / HL / NHLBI NIH HHS / United States
HHSN268200900019C / HL / NHLBI NIH HHS / United States
N01HC95160 / HL / NHLBI NIH HHS / United States
S10 OD018526 / OD / NIH HHS / United States
K08 HL118128 / HL / NHLBI NIH HHS / United States
N01HC95163 / HL / NHLBI NIH HHS / United States
UL1 TR001079 / TR / NCATS NIH HHS / United States
R01 HL112986 / HL / NHLBI NIH HHS / United States
K24 HL137013 / HL / NHLBI NIH HHS / United States
N01HC95164 / HL / NHLBI NIH HHS / United States
N02HL64278 / HL / NHLBI NIH HHS / United States
N01HC95162 / HL / NHLBI NIH HHS / United States
R01 HL093081 / HL / NHLBI NIH HHS / United States
N01HC95168 / HL / NHLBI NIH HHS / United States
HHSN268200900015C / HL / NHLBI NIH HHS / United States
U01 HL137880 / HL / NHLBI NIH HHS / United States
N01HC95159 / HL / NHLBI NIH HHS / United States
N01HC95161 / HL / NHLBI NIH HHS / United States
UL1 TR001420 / TR / NCATS NIH HHS / United States
HHSN268200900018C / HL / NHLBI NIH HHS / United States
P30 DK054759 / DK / NIDDK NIH HHS / United States
N01HC95167 / HL / NHLBI NIH HHS / United States
R01 HL130506 / HL / NHLBI NIH HHS / United States
HHSN268200900017C / HL / NHLBI NIH HHS / United States
HHSN268200900020C / HL / NHLBI NIH HHS / United States
HHSN268200900013C / HL / NHLBI NIH HHS / United States
UL1 TR000040 / TR / NCATS NIH HHS / United States
N01HC95166 / HL / NHLBI NIH HHS / United States
K23 HL130627 / HL / NHLBI NIH HHS / United States
UL1 TR001881 / TR / NCATS NIH HHS / United States
HHSN268200900014C / HL / NHLBI NIH HHS / United States
R01 HL131565 / HL / NHLBI NIH HHS / United States
MS#: 
MS119
Manuscript Full Title: 
A Genetic Risk Score Associated with Chronic Obstructive Pulmonary Disease Susceptibility and Lung Structure on Computed Tomography.
Manuscript Lead/Corresponding Author Affiliation: 
Clinical Center: New York (Columbia University)
ECI: 
Manuscript Status: 
Published and Public