Introduction: Among those who develop severe COPD and advanced emphysema, a small subset of up to 2-3% possesses polymorphisms of the SERPINA1 gene, associated with alpha-1 antitrypsin deficiency (AATD). The current study aimed to identify the frequency of genetic variants in genes known to be associated with COPD in a group of patients with severe airflow obstruction and advanced emphysema.

Methods: Whole exome DNA sequencing (WES) was conducted COPD patients with advanced emphysema (n=169) to investigate the prevalence of SERPINA1 mutations and variants within telomere length related genes (TERC, TERT and NAF1). AAT serum levels were measured by ELISA. The frequency of the variants was compared with a general population of non-Hispanic white COPD patients (SPIROMICS). Emphysema was measured using CT scan using -950 Hounsfield units (ES950).

Results: In the current study we found the Z-allele to be >4x more prevalent at 13%, compared to 3% in general COPD patients (SPIROMICS). As expected, patients with the SERPINA1 pathogenic alleles exhibited significantly lower AAT serum levels (p<0.0001). The overall degree of emphysema was not linked to AATD-related variants; however, patients with complete loss of SERPINA1 showed a lower ratio between upper/lower lobe ES950 indicating lower lobes predominate emphysema (p<0.01). A novel mutation was identified in NAF1 (p.Val3Ile) and 2 novel mutations in TERT (p.Arg48Cys and p.Arg108Ser).

Conclusion: Our study showed that AATD variants are more prevalent in COPD patients with emphysema than in the general COPD patient population and were associated with emphysema predominance in the lower lobes. In addition, we found novel potentially pathogenic mutations in NAF1 and TERT.