Rationale: The ZZ genotype of alpha-1 antitrypsin deficiency (AATD) is associated with chronic obstructive pulmonary disease (COPD), even among never-smokers. The SZ genotype is also considered severe; yet, its effect on lung health remains unclear.Objectives: To determine the effect of SZ-AATD on spirometry compared with a normal-risk population and to determine the effect of smoking cessation in this genotype.Methods: We prospectively enrolled 166 related individuals, removing lung index cases to reduce bias, and compared spirometry between 70 SZ and 46 MM/MS individuals (control subjects). The effect of AAT concentrations on outcomes was assessed in 82 SZ individuals (including lung index cases). Subsequently, we analyzed retrospective SZ registry data to determine the effect of smoking cessation on spirometry decline (n = 60) and plasma anti-neutrophil elastase capacity (n = 20).Measurements and Main Results: No difference between SZ and control never-smokers was seen. Ever smoking was associated with a lower FEV1% predicted (-14.3%; P = 0.0092) and a lower FEV1/FVC ratio (-0.075; P = 0.0041) in SZ-AATD. No association was found between AAT concentration and outcomes for SZ-AATD. Longitudinal analysis of 60 SZ individuals demonstrated that COPD at baseline, but not former smoking or AAT concentrations, predicted greater spirometry decline. Finally, anti-neutrophil elastase capacity did not differ between former smokers and never-smokers (P = 0.67).Conclusions: SZ never-smokers demonstrated no increased risk of COPD, regardless of AAT concentration. Smoking interacts with SZ-AATD to significantly increase airflow obstruction. Former smoking alone is not associated with greater spirometry decline in SZ-AATD, suggesting that cessation attenuates the obstructive process. We found no evidence that the putative protective threshold or AAT concentrations predict risk within the SZ genotype, raising further doubts over the need for intravenous AAT augmentation in this cohort.
Keywords: PiSZ; chronic obstructive pulmonary disease; genotype; phenotype.