Abstract
Background: α1-antitrypsin deficiency (AATD) is a known genetic risk factor for emphysema. Despite severe deficit many AATD individuals do not develop emphysema, suggesting that other genetic modifiers could contribute to the disease.
Aim: To identify susceptibility genes acting as possible co-factors for emphysema development in AATD siblings.
Methods: DNA extracted from peripheral blood was analyzed by whole-exome sequencing (WES) on 4 pairs of siblings concordant for genotype (Z/Z or Z/Q0brescia) but discordant for presence of emphysema. Recessive and dominant inheritance models were evaluated in affected and not affected subjects. Non synonymous genetic variants confirmed in 3 families were prioritized using QueryOR. Functional and metabolic enrichment was verified with PANTHER, KEGG and Reactome; Cytoscape was used to create network with enriched pathways.
Results: In affected subjects we identified 14 genes segregating in the recessive and 21 genes in the dominant model. Conversely, in not affected subjects we found 21 genes in the recessive and 50 genes in the dominant model. Identified genes were mainly related to the immune system. Network analysis shows enrichment in pathways such as Antigen Processing, Class I MHC Antigen Presentation (affected), Interferon Gamma, TCR and PD-1 signaling (not affected).
Conclusion: We described for the first time possible genetic susceptibility factors for emphysema in AATD siblings. Our data suggest that gene variants involved in the regulation of immune homeostasis and the maintenance of self-tolerance could contribute to development or suppression of the disease.
Funded by CHEST/Alpha-1 Foundation; Padua University; San Matteo Hospital Pavia
Footnotes
Cite this article as: European Respiratory Journal 2018 52: Suppl. 62, PA1267.
This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).
- Copyright ©the authors 2018