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

Abstract

Rationale: 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.

Keywords: asthma; endotyping; metabo-endotypes; metabolomics.

Figure 1.

FEV₁/FVC ratio before and after bronchodilator (BD) demonstrating significant difference across metabo-endotypes in both the Genetics of Asthma in Costa Rica Study (GACRS) and the Childhood Asthma Management Program (CAMP). Mean and standard errors for the specified metric in each metabo-endotype are shown. P values are derived from a one-way ANOVA test comparing the continuous variables across the five metabo-endotypes.

Figure 2.

Chemical similarity enrichment analysis of (A) metabo-endotype 2 membership versus membership in any other metabo-endotype and (B) metabo-endotype 2 membership versus membership in any other metabo-endotype. Figures include all enriched metabolite sets based on false discovery rate < 0.05. Each circle represents a set; circle sizes represent the total number of metabolites in each set. The color corresponds to the proportion of increased (red) or decreased (blue) compounds. Purple circles have both increased and decreased metabolites. The y-axis shows the significance of the enrichment for a given metabolite set. The x-axis shows the median XlogP of clusters, which is a measure of the average lipophilicity of the set, based on the octanol/water partition of the component metabolites. FA = fatty acids; HETE = hydroxyeicosatetraenoic acids; OH-FA = hydroxy-fatty acids.