Individuals with Alpha-1 antitrypsin deficiency (AATD) PiZZ genotype, have an increased risk of developing lung and/or liver disease, although not all of them develop the same manifestations, which suggests the presence of modifier genetic variants that favor a specific phenotype. These genetic factors are mostly unknown, but they could help to identify patients with a higher risk of developing AATD-associated lung or liver disease.

In order to identify modifier genetic variants, we have sequenced the complete exome (Twist Human Core Exome Plus) of a group of 72 patients with AATD, all of them with the PiZZ genotype. Among these patients, 13 had liver disease (ZZ-HEP) and 59 had lung disease only (ZZ-PUL). After annotating the variants, an association analysis was performed comparing the frequencies in both groups ZZ-PUL and ZZ-HEP.

We found 537 genes with variants significantly associated with lung or liver disease (OR between 3-25, p>0.05), 412 variants presented higher frequency in ZZ-HEP and 125 variants were more frequent in ZZ-PUL. Among these variants, 14% produce amino acid changes in proteins, and 86% were non-coding intronic variants. The functional annotations of genes with significant variants were related to different pathways such as transport, bile acid synthesis, apoptosis, biological oxidations, metabolism, proteases, PTEN regulation, or macroautophagy.

Our results identified genetic variants that confer specific risk of lung or liver damage in PiZZ patients, and that could contribute to stratify patients identifying those at higher risk of suffering AATD lung or liver associated disease.