Towards precision medicine: The application of omics technologies in asthma management

What else could be done for the management of severe asthma

Omics technology supports precision medicine in identifying the most effective treatment for different clinical phenotypes, in contrast with the “one size fits all” approach. Indeed, omics sciences contribute to the definition of new biomarkers, which can be useful as hallmarks of a specific asthma endotype or phenotype, and relevant as novel targets for pharmacology treatments. In the field of molecular biology, omics is a neologism that indicates high-throughput experimental technologies providing the tools for comprehensively monitoring the disease processes at a molecular level. The suffix “ome” comes from “chromosome” and currently includes several biological fields such as genomics, transcriptomics, proteomics, metabolomics and epigenomics. Genomics and transcriptomics have been using to identify genes associated with asthma severity (Figure 1). Recent genome-wide association studies (GWAS) have shed light on distinct pathways that contribute to asthma inflammation. Genes such as HLA, IL13, IL33, thymic stromal lymphopoietin (TSLP) involved in Th2 pathway, IL-1 receptor–like 1 (IL1RL1), encodes ST2, and the receptor for IL-33 are associated with asthma onset. In contrast, it is well-known that the risk of childhood asthma is associated with the 17q21 locus encoding the ORMDL3 and GSDML genes^6,7. Transcriptomics are focused on the identification of an increasing number of several types of RNA with different function, e.g messenger RNAs (mRNAs) and long non coding RNAs (lncRNAs) but particular attention should be given to the investigation of microRNAs (miRNAs). MiRNAs are small non-coding single strand RNA chains involved in post-transcriptional regulation processes. MiRNAs play a key role in regulating cell functions as well as in modulating the inflammatory pathways. They may influence the single endotype profile in the complex asthma phenotype picture, therefore, the relevance of miRNA as a biomarker has been increasingly investigating. MiRNAs can be collected through peripheral blood sampling (Circulating miRNA), or, more invasively, through bronchial biopsies and induced sputum^8,9. Circulating miRNA deserves a specific interest, because they might be a non-invasive biomarker useful in asthma diagnosis and characterisation, as demonstrated in a recent study. According to the authors, a specific subset of circulating miRNAs (miR-125b, miR-16, miR-299-5p, miR-126, miR-206, and miR-133b) was found in patients with allergic rhinitis and asthma¹⁰. MiRNA 192 in peripheral blood was under-expressed in blood of asthmatic patients underwent an allergen inhalation challenge¹¹. Different levels of miR-1248 in serum of asthmatic vs non-asthmatic patients have been also documented. MiR-1248 is involved in the regulation of IL-5 pathway¹¹.

Figure 1. A systems biology approach: From omics science to precision medicine.

Epigenomics includes DNA methylation, histone modifications and non-coding RNAs previously described. Its role is to control gene expression acting on DNA structure. Several genes related to asthma are regulated by epigenetic mechanism such as genes involved in T-effector pathways (Interferon INF-γ, Ιnterleukin (IL)-4, IL-13 and IL-17), T-regulatory pathways (forkhead box P3 [FoxP3]) and airway inflammation (arginase [ARG])¹². The “methylome” (the set of DNA methylation patterns) has been increasingly investigating through highly sophisticated sequence-based assays. Epigenetic mechanisms could lead to the identification of new asthma biomarkers. Recently, an epigenetic association between serum IgE concentration and methylation at different loci derived from DNA of leukocites has been described. Methylation at these CpG islands differed significantly in isolated eosinophils between subjects with and without asthma and high IgE levels¹³.

Modern and advanced technologies, such as mass spectrometry, allow the detection of several proteins involved in the inflammatory mechanisms of asthma. Today several biomarkers can identify Th2-high endotypes (serum IgE, serum periostin, blood eosinophil, exhaled nitric oxide eNO, dipeptidyl peptidase 4 (DPP-4 serum) in sputum. Among the proteomics signatures characterized so far, Galectin-3 deserves to be mentioned. It was indeed demonstrated that this protein is expressed in omalizumab responders only. Furthermore, galectin–3 seems to be associated with a more evident improvement of respiratory function in asthmatic patients treated with omalizumab¹⁴.

The increasing interest in metabolomics, is mainly due to its prospective clinical applications. Metabolomics could play an important role in measuring the concentrations of the metabolites generated in living system. According to recent findings it is possible to define the metabolic profile through different matrix including exhaled breath, urine, plasma and serum^15,16, Exhaled breath condensate (EBC) is a promising tool for the detection of asthma biomarkers. This biological sample could be used as a natural matrix of the respiratory tract, carrying useful biomarkers which allow to monitor changes in inflammatory airways diseases¹⁷. As recently demonstrated, electronic nose (eNose) and nuclear magnetic resonance (NMR)-based metabolomics could play a role in phenotyping chronic airway disease regardless of the diagnosis of asthma or COPD, suggesting therapeutical targets for a tailored respiratory medicine¹⁸. EBC contains different inorganic molecular species such as nitric oxide (NO) and carbon monoxide (CO) and also volatile organic compounds. Currently a branch of metabolomics called “breathomics” focuses on VOCs from the respiratory tract. VOCs represent potential non-invasive metabolic biomarkers, particularly in the diagnosis and monitoring of pulmonary diseases including asthma¹⁹. Moreover, an electronic nose able to discriminate asthmatic from healthy controls by detecting different VOCs in exhaled breath has been developed^19,20. Therefore, metabolomics could play a key role in identifying biomarkers and improving asthma endotyping.