Alpha-1 Antitrypsin MZ Heterozygosity Is an Endotype of Chronic Obstructive Pulmonary Disease

Abstract

Rationale: Multiple studies have demonstrated an increased risk of chronic obstructive pulmonary disease (COPD) in heterozygous carriers of the AAT (alpha-1 antitrypsin) Z allele. However, it is not known if MZ subjects with COPD are phenotypically different from noncarriers (MM genotype) with COPD. Objectives: To assess if MZ subjects with COPD have different clinical features compared with MM subjects with COPD. Methods: Genotypes of SERPINA1 were ascertained by using whole-genome sequencing data in three independent studies. We compared outcomes between MM subjects with COPD and MZ subjects with COPD in each study and combined the results in a meta-analysis. We performed longitudinal and survival analyses to compare outcomes in MM and MZ subjects with COPD over time. Measurements and Main Results: We included 290 MZ subjects with COPD and 6,184 MM subjects with COPD across the three studies. MZ subjects had a lower FEV₁% predicted and greater quantitative emphysema on chest computed tomography scans compared with MM subjects. In a meta-analysis, the FEV₁ was 3.9% lower (95% confidence interval [CI], -6.55% to -1.26%) and emphysema (the percentage of lung attenuation areas <-950 HU) was 4.14% greater (95% CI, 1.44% to 6.84%) in MZ subjects. We found one gene, PGF (placental growth factor), to be differentially expressed in lung tissue from one study between MZ subjects and MM subjects. Conclusions: Carriers of the AAT Z allele (those who were MZ heterozygous) with COPD had lower lung function and more emphysema than MM subjects with COPD. Taken with the subtle differences in gene expression between the two groups, our findings suggest that MZ subjects represent an endotype of COPD.

Keywords: RNA sequencing; alpha-1 antitrypsin; chronic obstructive pulmonary disease; meta-analysis.

Figure 1.

Meta-analysis of MZ effect sizes for lung function and computed tomographic emphysema. Meta-analyses of lung function and computed tomographic emphysema outcomes across the LTRC (Lung Tissue Research Consortium), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints), and COPDGene (Genetic Epidemiology of COPD) studies were conducted. MDs and 95% CIs are shown. Heterogeneity was estimated by using the DerSimonian-Laird method. (A) Meta-analysis of effect sizes of MZ genotype on the FEV₁% predicted. (B) Meta-analysis of effect sizes of the MZ genotype on the pctEmph. (C) Meta-analysis of effect sizes of the MZ genotype on the perc15. CI = confidence interval; COPD = chronic obstructive pulmonary disease; MD = mean difference; pctEmph = percentage of emphysema; perc15 = computed tomographic attenuation at the 15th percentile of the lung computed tomographic histogram.

Figure 2.

Survival in MM versus MZ subjects with chronic obstructive pulmonary disease (COPD) in the COPDGene (Genetic Epidemiology of COPD) and ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) studies. Kaplan-Meier curves demonstrating the survival probability in PI MM genotype subjects (orange lines) compared with PI MZ genotype subjects (teal lines) are shown. (A) Survival probability in the COPDGene study. (B) Survival probability in the ECLIPSE study.

Figure 3.

Pathway analysis of nominally significant differentially expressed genes and deconvoluted cell types between MM and MZ subjects with chronic obstructive pulmonary disease. Enrichment of Molecular Signatures Database hallmark pathways as determined by using nominally significant (P < 0.001) differentially expressed genes and selected cell-type deconvolution proportions are shown. (A) Pathways enriched in differentially expressed genes as determined by using RNA sequencing data from whole blood in the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) study. (B) Pathways enriched in differentially expressed genes as determined by using RNA sequencing data from lung tissue in the LTRC (Lung Tissue Research Consortium) study. (C) Selected deconvoluted cell-type proportions in the LTRC study, including neutrophils, B cells, CD8⁺ naive T cells, CD8⁺ nonnaive T cells, and macrophages. DN = down; padj = adjusted P value; UV = ultraviolet; V1 = version 1; V2 = version 2.