Identification of genetic modifying factors of lung disease in PI*ZZ Alpha-1 Antitrypsin Deficiency and their role in alveolar cells

<bold>Introduction:</bold> Individuals with PiZZ Alpha-1 Antitrypsin Deficiency (AATD) have an increased risk of developing lung and/or liver disease. Although environmental factors are known to influence on clinical phenotype, not all the phenotypic variation in AATD can be explained by them. The aim of this study was to identify genetic modifying factors of lung disease in patients with PiZZ AATD and investigate their relevance in alveolar cells. <bold>Material & methods:</bold> We performed a genetic association study with whole exome sequencing data of a group of 72 patients with PiZZ AATD. Thirteen patients had liver damage (ZZ-LIV) and 59 had lung-only disease (ZZ-LUN). Variants significantly associated with lung disease were functionally annotated and the genes involved were investigated in alveolar organoids. <bold>Results:</bold> We have identified 240 variants in 133 genes that appear more frequently in ZZ-LUN cases. These variants suppose 26% of the significant variants associated with either of the ZZ-LIV or ZZ-LUN groups. Eighty-six percent (86%) of the ZZ-LUN variants are non-coding variants located in intronic areas but which could have an effect on gene regulation. Some of the variants are located in genes with a role in neutrophil recruitment, surfactant production, proteases and in lung function and inflammation, and have been analysed in alveolar organoids. <bold>Conclusions:</bold> Our results have allowed us to identify genetic variants that could confer risk of lung disease in PiZZ patients. These variants could be new biomarkers of disease and help in patient stratification, although validation in a larger series of patients with AATD is needed.