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

Research output: Contribution to journalArticlepeer-review


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 ChronicObstructive 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. Singlenucleotide polymorphism-, gene-, and pathway-based approaches were used. In silico functional evaluation was also performed. Measurements and Main Results: Weidentified five loci associated with emphysema distribution at genome-wide significance. These loci included two previously reported associationswith COPDsusceptibility (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 (NCT 00608764).

Original languageEnglish (US)
Pages (from-to)757-771
Number of pages15
JournalAmerican journal of respiratory and critical care medicine
Issue number6
StatePublished - Mar 15 2017


  • Chronic obstructive pulmonary disease
  • Emphysema
  • Emphysema distribution
  • Genetics

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine


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