Abstract Rationale Alpha-1 antitrypsin deficiency (AATD) predisposes individuals to chronic obstructive pulmonary disease, particularly among smokers. The MZ genotype which causes moderate AAT deficiency is common, affecting approximately 2-5% of the global population, yet the risk factors and mechanisms of disease in this group remain poorly defined. This study examines longitudinal lung function decline, biochemical and cellular characteristics in MZ individuals and explores the impact of smoking, air quality and social deprivation on disease progression. Methods A total of 300 MZ individuals were analysed from the Irish National AATD Registry (median follow-up 6.2 years). Demographics, smoking status, spirometry, oscillometry and CT imaging were collated. Air pollutant data (PM2.5, PM10, NO2, O3) was sourced from the Environmental Protection Agency monitoring networks and regional deprivation indices from Pobal HP data. Longitudinal FEV1 decline was analysed using mixed-effects models adjusted for age, sex, and smoking history. A subset of individuals (n = 160) underwent biochemical and cellular characterisation. Serum analyses included inflammatory cytokines, antiprotease capacity, markers of extracellular matrix remodelling and M:Z protein and polymer ratio. A smaller subgroup (n = 20), underwent bronchoscopy and bronchoalveolar lavage (BAL) was analysed for protease–antiprotease balance and cellular phenotyping. Results Among 300 participants, 48% were past-smokers, 38% never-smokers and 13% active smokers. At diagnosis active smokers had established airway obstruction (median FEV1/FVC ratio 0.63) and significantly lower median FEV1 (78% predicted) than past smokers (median FEV1 89.5% predicted, median FEV1/FVC ratio 0.72) or never-smokers (median FEV1 104% predicted, median FEV1/FVC ratio 0.74). FEV1 decline was greatest in active smokers. CT imaging showed emphysema in 12%, bronchiectasis in 24%, combined emphysema and bronchiectasis in 7%, 43% had no abnormality reported and 14% had incidental findings (e.g nodules). CT densitometry results are pending. Higher social deprivation scores correlated with lower baseline FEV1 at diagnosis, particularly in smokers, while pollutant exposure showed inconsistent associations. Preliminary biochemical and BAL data demonstrate increased neutrophil elastase activity and pro-inflammatory cytokines in MZ compared with MM controls. Conclusions This study confirms smoking as the key driver of lung function decline in MZ AATD, with socioeconomic factors further accelerating disease progression. Smoking cessation attenuates this decline. Preliminary biochemical and BAL analyses indicate a distinct MZ endotype. These results reinforce the need for increased screening, early smoking cessation interventions and tailored clinical monitoring in this large susceptible cohort. This abstract is funded by: None
Breathnach et al. (Fri,) studied this question.