Does level or genotype determine lung risk in alpha-1 antitrypsin deficiency?

Introduction Alpha-1 antitrypsin deficiency (AATD) is characterised by low plasma alpha-1 antitrypsin (AAT) levels and increased risk of lung, liver and skin disease. Disease risk is presumed to be inversely proportional to plasma AAT level. The common AATD variants are S (p.Glu288Val) and Z (p.Glu366Lys), with S causing mild and Z causing severe deficiency. A single Z allele is associated with increased chronic obstructive pulmonary disease risk despite AAT levels above the putative protective threshold of 11 µM. Methods We evaluated the impact of AAT level and genotype on lung disease by comparing individuals with the MZ and SS genotypes with comparable plasma AAT levels to determine whether differences in disease phenotype are attributable to a single Z allele. Using a national AATD registry, we compared characteristics at diagnosis and longitudinal lung function. We also assessed antineutrophil elastase capacity (ANEC), AAT polymer burden and inflammatory markers. Results Analysis of 164 MZ and 54 SS individuals showed comparable age at diagnosis, smoking history, ANEC and AAT levels (0.85 g/L vs 0.88 g/L; p=0.138). MZ individuals had lower forced expiratory volume in 1 s (FEV1)% predicted (93% vs 101%; p=0.043) and FEV1/forced vital capacity (FVC) (72.7% vs 79%; p=0.001) at diagnosis, which persisted following multivariable adjustment (FEV1% predicted: β=−10.53, p=0.037; FEV1/FVC: β=−9.44, p=0.001). Age-related lung function decline differed significantly by genotype (FEV1% predicted, p=0.038; FEV1/FVC, p=0.024), with greater decline in MZ individuals. Circulating AAT polymer levels were higher in MZ than SS individuals (13.47 vs 2.54 ug/ml; p<0.001). Discussion MZ and SS individuals with similar circulating AAT concentrations and ANEC showed distinct lung function trajectories and disease phenotypes. AAT genotype may provide additional information beyond AAT level alone when assessing disease risk. These findings support a pro-inflammatory role for the Z allele in disease progression and have implications for therapies that both increase AAT levels and reduce Z expression and polymerisation.