Identifying biomarkers for asthma diagnosis using targeted metabolomics approaches

Abstract

Background The diagnosis of asthma in children is challenging and relies on a combination of clinical factors and biomarkers including methacholine challenge, lung function, bronchodilator responsiveness, and presence of airway inflammation. No single test is diagnostic. We sought to identify a pattern of inflammatory biomarkers that was unique to asthma using a targeted metabolomics approach combined with data science methods. Methods We conducted a nested case-control study of 100 children living in a peri-urban community in Lima, Peru. We defined cases as children with current asthma, and controls as children with no prior history of asthma and normal lung function. We further categorized enrollment following a factorial design to enroll equal numbers of children as either overweight or not. We obtained a fasting venous blood sample to characterize a comprehensive panel of targeted markers using a metabolomics approach based on high performance liquid chromatography-mass spectrometry. Results A statistical comparison of targeted metabolites between children with asthma (n = 50) and healthy controls (n = 49) revealed distinct patterns in relative concentrations of several metabolites: children with asthma had approximately 40–50% lower relative concentrations of ascorbic acid, 2-isopropylmalic acid, shikimate-3-phosphate, and 6-phospho-d-gluconate when compared to children without asthma, and 70% lower relative concentrations of reduced glutathione (all p < 0.001 after Bonferroni correction). Moreover, a combination of 2-isopropylmalic acid and betaine strongly discriminated between children with asthma (2-isopropylmalic acid ≤ 13 077 normalized counts/second) and controls (2-isopropylmalic acid > 13 077 normalized counts/second and betaine ≤ 16 47 121 normalized counts/second). Conclusions By using a metabolomics approach applied to serum, we were able to discriminate between children with and without asthma by revealing different metabolic patterns. These results suggest that serum metabolomics may represent a diagnostic tool for asthma and may be helpful for distinguishing asthma phenotypes.

Metabolic interactions in asthma

“…The increased phosphocholine levels, an important component of the endothelial cell barrier, in the serum of patients, indicates a lack of airways protection (8,9). Moreover, the release of reactive oxygen species (ROS) by inflammatory cells and the decrease in glutathione levels, leads to oxidative stress which triggers lipid peroxidation of the polyunsaturated fatty acids (PUFAs) of cells, reducing the ability of the epithelium for damage repair (8,11,17). The resultant metabolites are compiled in a systematic review (27).…”

“…The resultant metabolites are compiled in a systematic review (27). End products of lipid peroxidation are mainly hydrocarbons including hexane, heptane, pentanal, heptanal, decanal, octane, nonadecane, 4-methylheptane, 2,4-dimethylheptane 2,4-dimethylpentane, 2-methylpentane and other alkanes and aldehydes (13)(14)(15)(16)(17)(27)(28)(29). Interestingly, in elite swimmers, both with or without asthma, swimming was associated with a decrease in oxidative stress markers (30).…”

“…GSH, as an antioxidant, plays an important role to prevent oxidative stress and its pathway can be a target for some cases of CS resistance. Moreover, lower levels of ascorbic acid were reported in the serum of children with asthma (17). Ascorbic acid has an important role in protecting lung tissues, especially the alveoli, against oxidative stress, and decreased levels were associated with pulmonary dysfunction (37).…”

Chiral separation of disease biomarkers with 2‐hydroxycarboxylic acid structure

“…2‐Hydroxycaproic acid (2‐HCA) proved to be the most significant substance observed in the cerebrospinal fluid of a patient with Nocardia infection, an uncommon cause of meningitis . 2‐HBA, in the plasma, has been pointed out as a good marker for early stage type II diabetes and 2‐isopropylmalic acid (2‐IMA) has been described as a biomarker for asthma diagnosis . Related to cancer, altered concentrations of LA have been found in tumors , and the enantiomer D‐2‐HGA has been described as an oncometabolite .…”

A good asthma catch by professional fishing

“…This can be regarded as a significant limitation. However, let's face it: it may not be surprising that the few other metabolomic studies in asthma are not coming up with identical results [9]. The individual variability in host characteristics and environmental exposures of patients with asthma is likely to be huge, so we had better get used to findings that cannot be fully reproduced between and even within populations.…”