Metabo-Endotypes of Asthma Reveal Clinically Important Differences in Lung Function: Discovery and validation in two TOPMed Cohorts

Abstract Current guidelines do not sufficiently capture the heterogeneous nature of asthma; a detailed molecular classification is needed. Metabolomics represents a novel and compelling approach to derive asthma endotypes, i.e., subtypes defined by functional/pathobiological mechanisms. In two cohorts of asthmatics, untargeted metabolomic profiling and Similarity Network Fusion was used to derive and validate five “metabo-endotypes” of asthma, which displayed significant differences in asthma-relevant phenotypes including pre-bronchodilator and post-bronchodilator forced expiratory volume/forced vital capacity (FEV1/FVC). The “most-severe” asthma metabo-endotype was defined by the lowest FEV1/FVC and characterized by altered levels of phospholipids and polyunsaturated fatty acids, suggesting dysregulation of pulmonary surfactant homeostasis. This was supported by genetic analyses as members of this endotype were more likely to carry variants in key pulmonary surfactant regulation genes including BMPR1B (meta-analyzed p=2.8x10-4) and BMP3 (meta-analyzed p=5.23x10-4). These findings suggest clinically meaningful endotypes can be derived and validated using metabolomic data. Interrogating the drivers of these metabo-endotypes can help understand their pathophysiology.