Clinical consequences and longitudinal outcomes in PiMZ heterozygous a1-antitrypsin deficiency smokers from SPIROMICS

Background: The consequence of PiZ allele presence on lung function and emphysema in smokers from the SPIROMICS cohort were previously reported. The risk for accelerated lung function decline in heterozygous α-1 antitrypsin deficient smokers remains unclear. Focused on PiMZ heterozygosity as the most prevalent Z allele-containing genotype, we investigated its effects on baseline and longitudinal disease severity and progression. Methods: We identified 82 PiMZ and 2454 PiMM smokers without additional pathogenic SERPINA1 variation based on DNA sequencing. Baseline and longitudinal regression-based models included age, race, sex, smoking status and smoking history. Results: Compared to PiMM, PiMZ cohort was similar in age, sex, BMI, history of asthma and smoking, predominantly non-Hispanic white. PiMZ smokers had lower mean %predicted FEV1 (74.1±1.4 vs 65.9±3.1, p = 0.004) and were more likely to have emphysema based on normative equations for -950HU cutoff (OR 1.75, p=0.018). PiMZ smokers had a greater extent of parametric response mapping (PRM) emphysema (+3.4%, CI 0.4-6.3, p=0.027) but no significant difference in PRM functional small airway disease (+2.5%, CI -1.0-6.0, p=0.16) . In longitudinal models, there was a non-significant trend toward higher rate of severe exacerbations (SE) (RR=1.6, p=0.1), but no difference in mortality, the slope of FEV1 decline or SGRQ change over three years. Conclusion: Compared with PiMM genotype, smokers with PiMZ are more likely to have emphysema and with a trend towards more SE. Longer observational cohorts of PiMZ smokers are needed to characterize the natural history of lung disease in PiMZ heterozygotes.