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

RATIONALE Multiple studies have demonstrated an increased risk of chronic obstructive pulmonary disease (COPD) in heterozygous carriers of the alpha-1 antitrypsin Z allele. However, it is not known if MZ subjects with COPD are phenotypically different compared to non-carriers (MM genotype) with COPD. We hypothesized that MZ subjects with COPD have different clinical features compared to MM subjects with COPD. METHODS Genotypes of SERPINA1 were ascertained from whole genome sequencing data in three independent studies. We compared outcomes between MM 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. RESULTS We included 290 MZ subjects with COPD and 6,184 MM subjects with COPD across the three studies. MZ subjects had lower FEV1 % predicted and greater quantitative emphysema on chest CT scans compared to MM subjects. In a meta-analysis, FEV1 was 3.9% lower (95% CI -6.55, -1.26) and emphysema (percent of lung attenuation areas < -950HU) was 4.14% greater (95% CI 1.44, 6.84) in MZ subjects. We found one gene, PGF, differentially expressed in lung tissue from one study between MZ subjects compared to MM subjects. CONCLUSIONS Carriers of the alpha-1 antitrypsin Z allele (MZ heterozygotes) with COPD had lower lung function and more emphysema compared to 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.