PMID- 27669027

OWN - NLM
STAT- MEDLINE
DCOM- 20170719
LR - 20210804
IS - 1535-4970 (Electronic)
IS - 1073-449X (Print)
IS - 1073-449X (Linking)
VI - 195
IP - 6
DP - 2017 Mar 15
TI - Genome-Wide Association Study of the Genetic Determinants of Emphysema
Distribution.
PG - 757-771
LID - 10.1164/rccm.201605-0997OC [doi]
AB - RATIONALE: Emphysema has considerable variability in the severity and
distribution of parenchymal destruction throughout the lungs. Upper
lobe-predominant emphysema has emerged as an important predictor of response
to
lung volume reduction surgery. Yet, aside from alpha-1 antitrypsin
deficiency,
the genetic determinants of emphysema distribution remain largely unknown.
OBJECTIVES: To identify the genetic influences of emphysema distribution in
non-alpha-1 antitrypsin-deficient smokers. METHODS: A total of 11,532
subjects
with complete genotype and computed tomography densitometry data in the
COPDGene
(Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD];
non-Hispanic white and African American), ECLIPSE (Evaluation of COPD
Longitudinally to Identify Predictive Surrogate Endpoints), and GenKOLS
(Genetics
of Chronic Obstructive Lung Disease) studies were analyzed. Two computed
tomography scan emphysema distribution measures (difference between upper-
third
and lower-third emphysema; ratio of upper-third to lower-third emphysema)
were
tested for genetic associations in all study subjects. Separate analyses in
each
study population were followed by a fixed effect metaanalysis. Single-
nucleotide
polymorphism-, gene-, and pathway-based approaches were used. In silico
functional evaluation was also performed. MEASUREMENTS AND MAIN RESULTS: We
identified five loci associated with emphysema distribution at genome-wide
significance. These loci included two previously reported associations with
COPD
susceptibility (4q31 near HHIP and 15q25 near CHRNA5) and three new
associations
near SOWAHB, TRAPPC9, and KIAA1462. Gene set analysis and in silico
functional
evaluation revealed pathways and cell types that may potentially contribute
to
the pathogenesis of emphysema distribution. CONCLUSIONS: This multicohort
genome-wide association study identified new genomic loci associated with
differential emphysematous destruction throughout the lungs. These findings
may
point to new biologic pathways on which to expand diagnostic and therapeutic
approaches in chronic obstructive pulmonary disease. Clinical trial
registered
with www.clinicaltrials.gov (NCT 00608764).
FAU - Boueiz, Adel
AU - Boueiz A
AD - 1 Channing Division of Network Medicine.
AD - 2 Pulmonary and Critical Care Division, Department of Medicine, and.
FAU - Lutz, Sharon M
AU - Lutz SM
AD - 3 Department of Biostatistics, Colorado School of Public Health, University
of
Colorado, Aurora, Colorado.
FAU - Cho, Michael H
AU - Cho MH
AD - 1 Channing Division of Network Medicine.
AD - 2 Pulmonary and Critical Care Division, Department of Medicine, and.
FAU - Hersh, Craig P
AU - Hersh CP
AD - 1 Channing Division of Network Medicine.
AD - 2 Pulmonary and Critical Care Division, Department of Medicine, and.
FAU - Bowler, Russell P
AU - Bowler RP
AD - 4 Division of Pulmonary Medicine, Department of Medicine, National Jewish
Health,
Denver, Colorado.
FAU - Washko, George R
AU - Washko GR
AD - 2 Pulmonary and Critical Care Division, Department of Medicine, and.
FAU - Halper-Stromberg, Eitan
AU - Halper-Stromberg E
AD - 4 Division of Pulmonary Medicine, Department of Medicine, National Jewish
Health,
Denver, Colorado.
FAU - Bakke, Per
AU - Bakke P
AD - 5 Department of Clinical Science, University of Bergen, Bergen, Norway.
FAU - Gulsvik, Amund
AU - Gulsvik A
AD - 5 Department of Clinical Science, University of Bergen, Bergen, Norway.
FAU - Laird, Nan M
AU - Laird NM
AD - 6 Harvard School of Public Health, Boston, Massachusetts.
FAU - Beaty, Terri H
AU - Beaty TH
AD - 7 Bloomberg School of Public Health, Johns Hopkins University, Baltimore,
Maryland; and.
FAU - Coxson, Harvey O
AU - Coxson HO
AD - 8 Department of Radiology, University of British Columbia, Vancouver, British

Columbia, Canada.
FAU - Crapo, James D
AU - Crapo JD
AD - 4 Division of Pulmonary Medicine, Department of Medicine, National Jewish
Health,
Denver, Colorado.
FAU - Silverman, Edwin K
AU - Silverman EK
AD - 1 Channing Division of Network Medicine.
AD - 2 Pulmonary and Critical Care Division, Department of Medicine, and.
FAU - Castaldi, Peter J
AU - Castaldi PJ
AD - 1 Channing Division of Network Medicine.
AD - 9 Division of General Medicine and Primary Care, Brigham and Women's
Hospital,
Harvard Medical School, Boston, Massachusetts.
FAU - DeMeo, Dawn L
AU - DeMeo DL
AD - 1 Channing Division of Network Medicine.
AD - 2 Pulmonary and Critical Care Division, Department of Medicine, and.
CN - COPDGene and ECLIPSE Investigators
LA - eng
SI - ClinicalTrials.gov/NCT00608764
SI - ClinicalTrials.gov/NCT00292552
GR - R01 HL113264/HL/NHLBI NIH HHS/United States
GR - R01 HL089897/HL/NHLBI NIH HHS/United States
GR - R25 ES011080/ES/NIEHS NIH HHS/United States
GR - T32 ES007142/ES/NIEHS NIH HHS/United States
GR - U01 HL089897/HL/NHLBI NIH HHS/United States
GR - R01 HL089856/HL/NHLBI NIH HHS/United States
GR - U01 HL089856/HL/NHLBI NIH HHS/United States
GR - K08 HL141601/HL/NHLBI NIH HHS/United States
GR - R01 HL126596/HL/NHLBI NIH HHS/United States
GR - K12 HL120004/HL/NHLBI NIH HHS/United States
GR - R01 HL124233/HL/NHLBI NIH HHS/United States
GR - P01 HL114501/HL/NHLBI NIH HHS/United States
GR - T32 HL007427/HL/NHLBI NIH HHS/United States
GR - K01 HL125858/HL/NHLBI NIH HHS/United States
GR - S10 OD018526/OD/NIH HHS/United States
PT - Journal Article
PT - Research Support, N.I.H., Extramural
PT - Research Support, Non-U.S. Gov't
TA - Am J Respir Crit Care Med
JT - American journal of respiratory and critical care medicine
JID - 9421642
SB - IM
MH - Cohort Studies
MH - Female
MH - Genetic Predisposition to Disease/*genetics
MH - Genome-Wide Association Study/*methods
MH - Humans
MH - Lung/diagnostic imaging/physiopathology
MH - Male
MH - Middle Aged
MH - Pulmonary Emphysema/diagnostic imaging/*genetics/physiopathology
MH - Smoking/physiopathology
MH - Tomography, X-Ray Computed
PMC - PMC5363968
OTO - NOTNLM
OT - *chronic obstructive pulmonary disease
OT - *emphysema
OT - *emphysema distribution
OT - *genetics
EDAT- 2016/09/27 06:00
MHDA- 2017/07/20 06:00
CRDT- 2016/09/27 06:00
PHST- 2016/09/27 06:00 [pubmed]
PHST- 2017/07/20 06:00 [medline]
PHST- 2016/09/27 06:00 [entrez]
AID - 10.1164/rccm.201605-0997OC [doi]
PST - ppublish
SO - Am J Respir Crit Care Med. 2017 Mar 15;195(6):757-771. doi:
10.1164/rccm.201605-0997OC.