Genome-Wide Association Study of the Genetic Determinants of Emphysema Distribution.
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.



To identify the genetic influences of emphysema distribution in non-alpha-1 antitrypsin-deficient smokers.



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.



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.



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).
1 Channing Division of Network Medicine.|2 Pulmonary and Critical Care Division, Department of Medicine, and.
Adel
A
Boueiz
3 Department of Biostatistics, Colorado School of Public Health, University of Colorado, Aurora, Colorado.
Sharon M
SM
Lutz
1 Channing Division of Network Medicine.|2 Pulmonary and Critical Care Division, Department of Medicine, and.
Michael H
MH
Cho
1 Channing Division of Network Medicine.|2 Pulmonary and Critical Care Division, Department of Medicine, and.
Craig P
CP
Hersh
4 Division of Pulmonary Medicine, Department of Medicine, National Jewish Health, Denver, Colorado.
Russell P
RP
Bowler
2 Pulmonary and Critical Care Division, Department of Medicine, and.
George R
GR
Washko
4 Division of Pulmonary Medicine, Department of Medicine, National Jewish Health, Denver, Colorado.
Eitan
E
Halper-Stromberg
5 Department of Clinical Science, University of Bergen, Bergen, Norway.
Per
P
Bakke
5 Department of Clinical Science, University of Bergen, Bergen, Norway.
Amund
A
Gulsvik
6 Harvard School of Public Health, Boston, Massachusetts.
Nan M
NM
Laird
7 Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland; and.
Terri H
TH
Beaty
8 Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada.
Harvey O
HO
Coxson
4 Division of Pulmonary Medicine, Department of Medicine, National Jewish Health, Denver, Colorado.
James D
JD
Crapo
1 Channing Division of Network Medicine.|2 Pulmonary and Critical Care Division, Department of Medicine, and.
Edwin K
EK
Silverman
1 Channing Division of Network Medicine.|9 Division of General Medicine and Primary Care, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Peter J
PJ
Castaldi
1 Channing Division of Network Medicine.|2 Pulmonary and Critical Care Division, Department of Medicine, and.
Dawn L
DL
DeMeo
D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008168:Lung / Q000000981:diagnostic imaging / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011656:Pulmonary Emphysema / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D012907:Smoking / Q000503:physiopathology; D014057:Tomography, X-Ray Computed
chronic obstructive pulmonary disease; emphysema; emphysema distribution; genetics
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