IREB2 and GALC are associated with pulmonary artery enlargement in chronic obstructive pulmonary disease

Abstract

Pulmonary hypertension is associated with advanced chronic obstructive pulmonary disease (COPD), although pulmonary vascular changes occur early in the course of the disease. Pulmonary artery (PA) enlargement (PAE) measured by computed tomography correlates with pulmonary hypertension and COPD exacerbation frequency. Genome-wide association studies of PAE in subjects with COPD have not been reported. To investigate whether genetic variants are associated with PAE within subjects with COPD, we investigated data from current and former smokers from the COPDGene Study and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study. The ratio of the diameter of the PA to the diameter of the aorta (A) was measured using computed tomography. PAE was defined as PA/A greater than 1. A genome-wide association study for COPD with PAE was performed using subjects with COPD without PAE (PA/A ≤ 1) as a control group. A secondary analysis used smokers with normal spirometry as a control group. Genotyping was performed on Illumina platforms. The results were summarized using fixed-effect meta-analysis. Both meta-analyses revealed a genome-wide significant locus on chromosome 15q25.1 in IREB2 (COPD with versus without PAE, rs7181486; odds ratio [OR] = 1.32; P = 2.10 × 10(-8); versus smoking control subjects, rs2009746; OR = 1.42; P = 1.32 × 10(-9)). PAE was also associated with a region on 14q31.3 near the GALC gene (rs7140285; OR = 1.55; P = 3.75 × 10(-8)). Genetic variants near IREB2 and GALC likely contribute to genetic susceptibility to PAE associated with COPD. This study provides evidence for genetic heterogeneity associated with a clinically important COPD vascular subtype.

Keywords: chronic obstructive pulmonary disease; genome-wide association; pulmonary hypertension; subtyping.

Figure 1.

Genome-wide association study design for subjects with chronic obstructive pulmonary disease (COPD) with a ratio of pulmonary artery (PA) diameter to aorta (A) diameter greater than 1. GOLD (Global Initiative for Chronic Obstructive Lung Disease) 2–4 was defined as having a post-bronchodilator forced expiratory volume at 1 second (FEV₁)/forced vital capacity (FVC) less than 0.7 and FEV₁ less than 80% predicted. Normal spirometry was defined as a post-bronchodilator FEV₁/FVC of 0.7 or greater and an FEV₁ of 80% predicted or greater. PAE, PA enlargement.

Figure 2.

The quantile–quantile plots (black) for the meta-analysis including 1,000 Genomes project imputed data of (A) subjects with COPD with PAE (PA/A > 1) versus those without PAE (PA/A ≤ 1), and (B) subjects with COPD with PAE versus smokers with normal spirometry, after adjustment for age, sex, pack-years of cigarette smoking, and genetic ancestry using principal components. The reference lines (blue) show the values where the observed (−logP) is equal to the expected (−logP).

Figure 3.

Manhattan plots of –log₁₀ P for the meta-analysis including 1,000 Genomes project imputed data of (A) subjects with COPD with PAE (PA/A > 1) versus those without PAE (PA/A ≤ 1), and (B) subjects with COPD with PAE versus smokers with normal spirometry, after adjustment for age, sex, pack-years of cigarette smoking, and genetic ancestry using principal components.

Figure 4.

Local association plots for genome-wide significant loci in the meta-analysis of subjects with COPD with PA/A greater than 1 versus subjects with COPD with PA/A of 1 or lower in COPDGene (Genetic Epidemiology of COPD) non-Hispanic whites (NHWs), African Americans (AAs), and ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints). The x axis is chromosomal position, and the y axis shows the –log₁₀ P value. The most significant single-nucleotide polymorphism (SNP) at each locus is labeled in purple, with other SNPs colored by degree of linkage disequilibrium (LD; r²). Plots were created using LocusZoom.

Figure 5.

Local association plots for significant loci in the meta-analysis of subjects with COPD with PA/A greater than 1 versus smoking control subjects in COPDGene NHWs, AAs, and ECLIPSE. The x axis is chromosomal position, and the y axis shows the –log₁₀ P value. The most significant SNP at each locus is labeled in purple (denoted by asterisk, as it is located in a transcription factor binding site conserved in a multiple-species alignment), with other SNPs colored by degree of LD (r²). Plots were created using LocusZoom.