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Clinical phenotypes in α1-antitrypsin deficiency: a cluster analysis on EARCO data
Anse Somers1,2, Kenneth Verstraete1,3,2, Ella Demesmaeker4
1Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium.
ERJ Open Research
|July 13, 2026
Summary
Alpha-1 antitrypsin deficiency (AATD) shows varied clinical presentations beyond genetics. Six distinct AATD phenotypes were identified, influenced by age at diagnosis, lung function, and smoking, aiding personalized research and treatment.
Area of Science:
- Genetics and Medicine
- Rare Diseases Research
Background:
- Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disorder causing lung and liver diseases.
- Clinical presentation of AATD is highly heterogeneous, even among individuals with the same genotype.
- This variability suggests significant environmental and epigenetic influences on AATD phenotypes.
Purpose of the Study:
- To identify and characterize distinct clinical phenotypes in Alpha-1 antitrypsin deficiency (AATD).
- To explore factors contributing to clinical heterogeneity in AATD beyond genetic predisposition.
Main Methods:
- Cluster analysis was performed on baseline data from the European Alpha-1 Research Collaboration (EARCO).
- The K-prototypes method was employed to identify patient clusters.
- A random forest classifier was used to determine key distinguishing features for the identified clusters.
Main Results:
- Six distinct clusters representing AATD clinical phenotypes were identified with a high cross-validated weighted F1 score (0.926).
- Key features differentiating these phenotypes include age at diagnosis, lung function, and tobacco consumption, alongside the AATD genotype.
- These findings highlight the multifactorial nature of AATD clinical presentation.
Conclusions:
- Clinical phenotypes in AATD are significantly influenced by factors beyond genotype.
- Integrating genetic, epigenetic, environmental, and behavioral data is crucial for understanding AATD heterogeneity.
- Longitudinal studies of these identified phenotypes will inform disease progression understanding and targeted therapy development.
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