• Am. J. Respir. Crit. Care Med. · Feb 2022

    Metabo-Endotypes of Asthma Reveal Differences in Lung Function: Discovery and Validation in two TOPMed Cohorts.

    • Rachel S Kelly, Kevin M Mendez, Mengna Huang, Brian D Hobbs, Clary B Clish, Robert Gerszten, Michael H Cho, Craig E Wheelock, Michael J McGeachie, Su H Chu, Juan C Celedón, Scott T Weiss, and Jessica Lasky-Su.
    • Channing Division of Network Medicine and.
    • Am. J. Respir. Crit. Care Med. 2022 Feb 1; 205 (3): 288299288-299.

    AbstractRationale: Current guidelines do not sufficiently capture the heterogeneous nature of asthma; a more detailed molecular classification is needed. Metabolomics represents a novel and compelling approach to derive asthma endotypes (i.e., subtypes defined by functional and/or pathobiological mechanisms). Objectives: To validate metabolomic-driven endotypes of asthma and explore their underlying biology. Methods: In the Genetics of Asthma in Costa Rica Study (GACRS), untargeted metabolomic profiling, similarity network fusion, and spectral clustering was used to identify metabo-endotypes of asthma, and differences in asthma-relevant phenotypes across these metabo-endotypes were explored. The metabo-endotypes were recapitulated in the Childhood Asthma Management Program (CAMP), and clinical differences were determined. Metabolomic drivers of metabo-endotype membership were investigated by meta-analyzing findings from GACRS and CAMP. Measurements and Main Results: Five metabo-endotypes were identified in GACRS with significant differences in asthma-relevant phenotypes, including prebronchodilator (p-ANOVA = 8.3 × 10-5) and postbronchodilator (p-ANOVA = 1.8 × 10-5) FEV1/FVC. These differences were validated in the recapitulated metabo-endotypes in CAMP. Cholesterol esters, trigylcerides, and fatty acids were among the most important drivers of metabo-endotype membership. The findings suggest dysregulation of pulmonary surfactant homeostasis may play a role in asthma severity. Conclusions: Clinically meaningful endotypes may be derived and validated using metabolomic data. Interrogating the drivers of these metabo-endotypes has the potential to help understand their pathophysiology.

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