Pharmacometabolomics of Bronchodilator Response in Asthma and the Role of Age-Metabolite Interactions.

Rachel S Kelly,Rachel S Kelly,Jessica Lasky-Su,Jessica Lasky-Su,Joanne E Sordillo,Ann Chen Wu,Ann Chen Wu,Amber Dahlin,Kelan Tantisira,Scott T Weiss,Scott T Weiss,Lydiana Avila,Juan C Celedón,Juan C Celedón,Joanne E Sordillo,Amber Dahlin,Kelan Tantisira,Clary B Clish,Mengna Huang,Mengna Huang,Michael J Mcgeachie,Michael J Mcgeachie,Sharon M Lutz,Sharon M Lutz,Manuel Soto-Quiros

doi:10.3390/metabo9090179

Abstract

The role of metabolism in modifying age-related differential responses to asthma medications is insufficiently understood. The objective of this study was to determine the role of the metabolome in modifying the effect of age on bronchodilator response (BDR) in individuals with asthma. We used longitudinal measures of BDR and plasma metabolomic profiling in 565 children with asthma from the Childhood Asthma Management Program (CAMP) to identify age by metabolite interactions on BDR. The mean ages at the three studied time-points across 16 years of follow-up in CAMP were 8.8, 12.8, and 16.8 years; the mean BDRs were 11%, 9% and 8%, respectively. Of 501 identified metabolites, 39 (7.8%) demonstrated a significant interaction with age on BDR (p-value < 0.05). We were able to validate two significant interactions in 320 children with asthma from the Genetics of Asthma in Costa Rica Study; 2-hydroxyglutarate, a compound involved in butanoate metabolism (interaction; CAMP: β = −0.004, p = 1.8 × 10−4; GACRS: β = −0.015, p = 0.018), and a cholesterol ester; CE C18:1 (CAMP: β = 0.005, p = 0.006; GACRS: β = 0.023, p = 0.041) Five additional metabolites had a p-value < 0.1 in GACRS, including Gammaminobutyric acid (GABA), C16:0 CE, C20:4 CE, C18.0 CE and ribothymidine. These findings suggest Cholesterol esters and GABA may modify the estimated effect of age on bronchodilator response.

Highlights

Asthma affects nearly 340 million people worldwide across all age groups and is responsible for roughly 1000 deaths every day [1]
Our results suggest that an inverse association between age and bronchodilator response (BDR) in asthmatics aged 5–25 years may be enhanced with higher levels of 2-hydroxyglutarate, while increased levels of cholesterol esters, Gammaminobutyric acid (GABA) and ribothymidine may attenuate the age-associated BDR decline
2-hydroxyglutarate has not previously been associated with lung function or asthma, it has been associated with hypoxia in primary cultures of lung cells [9]. 2-hydroxyglutarate is involved in the butanoate metabolism pathway, which regulates the GAD (Glutamic Acid Decarboxylase)-mediated decarboxylation of L-glutamate into

Summary

Introduction

Asthma affects nearly 340 million people worldwide across all age groups and is responsible for roughly 1000 deaths every day [1]. Metabolites 2019, 9, 179 asthma differs from that of adult-onset asthma, and treatment response varies by age [2], suggesting that age plays a role in the underlying mechanisms of asthma phenotypes across the life-course. Pharmaco-metabolomics is an emerging sub-discipline of metabolomics, which can be defined as the systematic analysis of the metabolites in a biological sample to improve understanding of the mechanistic effects of drugs, and the differences in response between individuals [3]. Metabolomics is well suited to the study of asthma, as it reflects underlying genetics, environmental exposures, and phenotype. Pharmaco-metabolomics has the potential to inform precision medicine initiatives against asthma

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