Dataset Information

A Genome-Wide Association Study of Emphysema and Airway Quantitative Imaging Phenotypes.

ABSTRACT: RATIONALE:Chronic obstructive pulmonary disease (COPD) is defined by the presence of airflow limitation on spirometry, yet subjects with COPD can have marked differences in computed tomography imaging. These differences may be driven by genetic factors. We hypothesized that a genome-wide association study (GWAS) of quantitative imaging would identify loci not previously identified in analyses of COPD or spirometry. In addition, we sought to determine whether previously described genome-wide significant COPD and spirometric loci were associated with emphysema or airway phenotypes. OBJECTIVES:To identify genetic determinants of quantitative imaging phenotypes. METHODS:We performed a GWAS on two quantitative emphysema and two quantitative airway imaging phenotypes in the COPDGene (non-Hispanic white and African American), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints), NETT (National Emphysema Treatment Trial), and GenKOLS (Genetics of COPD, Norway) studies and on percentage gas trapping in COPDGene. We also examined specific loci reported as genome-wide significant for spirometric phenotypes related to airflow limitation or COPD. MEASUREMENTS AND MAIN RESULTS:The total sample size across all cohorts was 12,031, of whom 9,338 were from COPDGene. We identified five loci associated with emphysema-related phenotypes, one with airway-related phenotypes, and two with gas trapping. These loci included previously reported associations, including the HHIP, 15q25, and AGER loci, as well as novel associations near SERPINA10 and DLC1. All previously reported COPD and a significant number of spirometric GWAS loci were at least nominally (P?

SUBMITTER: Cho MH

PROVIDER: S-EPMC4595690 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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A Genome-Wide Association Study of Emphysema and Airway Quantitative Imaging Phenotypes.

Cho Michael H MH Castaldi Peter J PJ Hersh Craig P CP Hobbs Brian D BD Barr R Graham RG Tal-Singer Ruth R Bakke Per P Gulsvik Amund A San José Estépar Raúl R Van Beek Edwin J R EJ Coxson Harvey O HO Lynch David A DA Washko George R GR Laird Nan M NM Crapo James D JD Beaty Terri H TH Silverman Edwin K EK

American journal of respiratory and critical care medicine 20150901 5

<h4>Rationale</h4>Chronic obstructive pulmonary disease (COPD) is defined by the presence of airflow limitation on spirometry, yet subjects with COPD can have marked differences in computed tomography imaging. These differences may be driven by genetic factors. We hypothesized that a genome-wide association study (GWAS) of quantitative imaging would identify loci not previously identified in analyses of COPD or spirometry. In addition, we sought to determine whether previously described genome-w ...[more]

PMID: 26030696

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Project description:RationaleEmphysema 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.ObjectivesTo identify the genetic influences of emphysema distribution in non-alpha-1 antitrypsin-deficient smokers.MethodsA 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 resultsWe 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.ConclusionsThis 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).

Dataset Information

A Genome-Wide Association Study of Emphysema and Airway Quantitative Imaging Phenotypes.

Publications

A Genome-Wide Association Study of Emphysema and Airway Quantitative Imaging Phenotypes.

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