Clinical phenotypes in α

Background: α-1 antitrypsin deficiency (AATD) is a rare, monogenic disorder predisposing individuals to liver and lung diseases. Yet, even within the same genotype, AATD is very heterogeneous in clinical presentation. This heterogeneity suggests a complex interplay of environmental and (epi)genetic factors, highlighting the need for a detection and study of clinical phenotypes. Methods: Here, we performed a cluster analysis using baseline data from the European Alpha-1 Research Collaboration (EARCO) to identify distinct clinical phenotypes in AATD. Results: We identified six clusters of AATD clinical phenotypes using K-prototypes with a cross-validated weighted F1 score of 0.926. Moreover, using a trained random forest classifier, we identified age at diagnosis, lung function and tobacco consumption as the most important features in distinguishing these clusters, in addition to the AATD-associated genotype. Conclusions: Overall, these findings underscore the fact that, beyond genotype, a multitude of other factors significantly influence AATD clinical phenotypes. Accordingly, this emphasises the importance of integrating (epi)genetic, environmental and behavioural data in future fundamental and translational research to unravel the complex mechanisms underlying patient heterogeneity. Moreover, longitudinal follow-up of individuals allocated to these clusters will help to better understand disease progression and to assess the potential benefits of specific therapies in different phenotypes.