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

Abstract

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).

Trial registration: ClinicalTrials.gov NCT00608764 NCT00292552.

Keywords: chronic obstructive pulmonary disease; emphysema; emphysema distribution; genetics.

Figures

Figure 1.

Participant flow diagrams of the studied cohorts: COPDGene (Genetic Epidemiology of COPD) NHW (non-Hispanic white subjects) (top left), COPDGene AA (African Americans) (bottom left), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) (top right), and GenKOLS (Genetics of Chronic Obstructive Lung Disease) (bottom right). COPD = chronic obstructive pulmonary disease; CT = computed tomography; GOLD = Global Initiative for Chronic Obstructive Lung Disease.

Figure 2.

Regional association plots for metaanalysis genome-wide significant loci. These plots were generated using the LocusZoom tool with hg19/1,000 Genomes Mar 2012 European as the reference panel for non-Hispanic white subjects and hg19/1,000 Genomes Mar 2012 African for African American subjects. chr = chromosome; diff950 = inverse normally transformed difference between upper-third and lower-third emphysema; ratio950 = inverse normally transformed ratio between upper-third and lower-third emphysema.

Figure 2.

Regional association plots for metaanalysis genome-wide significant loci. These plots were generated using the LocusZoom tool with hg19/1,000 Genomes Mar 2012 European as the reference panel for non-Hispanic white subjects and hg19/1,000 Genomes Mar 2012 African for African American subjects. chr = chromosome; diff950 = inverse normally transformed difference between upper-third and lower-third emphysema; ratio950 = inverse normally transformed ratio between upper-third and lower-third emphysema.

Figure 2.

Regional association plots for metaanalysis genome-wide significant loci. These plots were generated using the LocusZoom tool with hg19/1,000 Genomes Mar 2012 European as the reference panel for non-Hispanic white subjects and hg19/1,000 Genomes Mar 2012 African for African American subjects. chr = chromosome; diff950 = inverse normally transformed difference between upper-third and lower-third emphysema; ratio950 = inverse normally transformed ratio between upper-third and lower-third emphysema.

Figure 3.

Heatmap of Roadmap enhancer enrichment. Cell type–specific enhancer activity was measured for each of five loci representing the six metaanalysis lead single-nucleotide polymorphisms (SNPs; two of the lead SNPs, rs138544659 and rs12914385, were in linkage disequilibrium and counted as one locus). Enhancer activity in cell types from the ENCODE and Roadmap projects were evaluated for relevant SNPs at each locus and compiled into a matrix with cell types along the columns and loci along the rows. Cell-type descriptions were searched for key words related to immune, endothelial, and lung cells to identify the relevant lines and label their text in the heatmap. Immune cell-type labels are highlighted in green, lung cell types in blue, fibroblasts in yellow, and mesenchymal stem cells in red. No endothelial cell types displayed enhancer activity at the six loci. chr = chromosome.