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

Adel Boueiz; Sharon M Lutz; Michael H Cho; Craig P Hersh; Russell P Bowler; George R Washko; Eitan Halper-Stromberg; Per Bakke; Amund Gulsvik; Nan M Laird; Terri H Beaty; Harvey O Coxson; James D Crapo; Edwin K Silverman; Peter J Castaldi; Dawn L DeMeo; COPDGene Investigators; ECLIPSE Investigators

doi:10.1164/rccm.201605-0997OC

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

Journal article

Open access

Peer reviewed

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

Adel Boueiz, Sharon M Lutz, Michael H Cho, Craig P Hersh, Russell P Bowler, George R Washko, Eitan Halper-Stromberg, Per Bakke, Amund Gulsvik, Nan M Laird, …

American journal of respiratory and critical care medicine, Vol.195(6), pp.757-771

03/15/2017

DOI: 10.1164/rccm.201605-0997OC

PMCID: PMC5363968

PMID: 27669027

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Abstract

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).

Genetic Predisposition to Disease - genetics

Pulmonary Emphysema - physiopathology

Humans

Middle Aged

Male

Tomography, X-Ray Computed

Lung - diagnostic imaging

Lung - physiopathology

Pulmonary Emphysema - diagnostic imaging

Smoking - physiopathology

Pulmonary Emphysema - genetics

Female

Genome-Wide Association Study - methods

Cohort Studies

Details

Title: Subtitle: Genome-Wide Association Study of the Genetic Determinants of Emphysema Distribution
Creators: Adel Boueiz - 2 Pulmonary and Critical Care Division, Department of Medicine, and
Sharon M Lutz - 3 Department of Biostatistics, Colorado School of Public Health, University of Colorado, Aurora, Colorado
Michael H Cho - 2 Pulmonary and Critical Care Division, Department of Medicine, and
Craig P Hersh - 2 Pulmonary and Critical Care Division, Department of Medicine, and
Russell P Bowler - 4 Division of Pulmonary Medicine, Department of Medicine, National Jewish Health, Denver, Colorado
George R Washko - 2 Pulmonary and Critical Care Division, Department of Medicine, and
Eitan Halper-Stromberg - 4 Division of Pulmonary Medicine, Department of Medicine, National Jewish Health, Denver, Colorado
Per Bakke - 5 Department of Clinical Science, University of Bergen, Bergen, Norway
Amund Gulsvik - 5 Department of Clinical Science, University of Bergen, Bergen, Norway
Nan M Laird - 6 Harvard School of Public Health, Boston, Massachusetts
Terri H Beaty - 7 Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland; and
Harvey O Coxson - 8 Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada
James D Crapo - 4 Division of Pulmonary Medicine, Department of Medicine, National Jewish Health, Denver, Colorado
Edwin K Silverman - 2 Pulmonary and Critical Care Division, Department of Medicine, and
Peter J Castaldi - 9 Division of General Medicine and Primary Care, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
Dawn L DeMeo - 2 Pulmonary and Critical Care Division, Department of Medicine, and
COPDGene Investigators
ECLIPSE Investigators
Contributors: Eric A Hoffman (Contributor) - University of Iowa, Radiology
Resource Type: Journal article
Publication Details: American journal of respiratory and critical care medicine, Vol.195(6), pp.757-771
DOI: 10.1164/rccm.201605-0997OC
PMID: 27669027
PMCID: PMC5363968
NLM abbreviation: Am J Respir Crit Care Med
ISSN: 1073-449X
eISSN: 1535-4970
Publisher: United States
Grant note: R25 ES011080 / National Institute of Environmental Health Sciences R01 HL089856 / National Heart, Lung, and Blood Institute R01 HL126596 / National Heart, Lung, and Blood Institute R01 HL113264 / National Heart, Lung, and Blood Institute K12 HL120004 / National Heart, Lung, and Blood Institute R01 HL124233 / National Heart, Lung, and Blood Institute R01 HL089897 / National Heart, Lung, and Blood Institute U01 HL089897 / National Heart, Lung, and Blood Institute T32 ES007142 / National Institute of Environmental Health Sciences S10 OD018526 / Office of the Director U01 HL089856 / National Heart, Lung, and Blood Institute K01 HL125858 / National Heart, Lung, and Blood Institute T32 HL007427 / National Heart, Lung, and Blood Institute P01 HL114501 / National Heart, Lung, and Blood Institute
Language: English
Date published: 03/15/2017
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Radiology; Internal Medicine
Record Identifier: 9984051791202771

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