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What genes are associated with asthma exacerbations?

In a recent study published in the Journal of Investigational Allergology and Clinical Immunology, researchers reviewed the genomics, transcriptomics, and epigenetics of asthma exacerbations (AEs).

Study: Asthma exacerbations: the genes behind the scenes. Image Credit: Rybalchenko Nadezhda/Shutterstock

AEs are episodes of aggravating symptoms that can be severe, warranting a change in treatment. Although multiple definitions have been reported in the literature for AE events, commonly, AE events comprise asthma-associated emergency department visits, hospitalizations, and the use of systemic corticosteroids. AEs represent a significant public health concern and are prioritized in asthma research.

Approximately 4000 deaths occur annually in the United States (US) and 15,000 in the United Kingdom (UK). The annual asthma healthcare expenditures cost around $50.3 billion in the US and £1.1 in the UK. Indirect costs of asthma (school/work absences) further contribute to the economic impact of asthma. In addition, AEs significantly affect asthmatic individuals’ quality of life (QoL) and their caregivers.

It is critical to identify relevant biomarkers/predictors of AEs to guide the prevention/reduction of AEs. Evidence suggests ethnic differences in AE patterns across the world. Puerto Ricans and African Americans in the US show higher rates of AEs, whereas Southern European countries have higher rates of AEs.

In the present review, researchers discussed the latest findings from Omics studies of AEs and assessed associated methodological challenges. The PubMed database was searched for genomic, transcriptomic, and epigenetic studies on AEs using several key terms. Reviews, opinion articles, editorials, studies involving animal/cell lines, and those without Omics/candidate-gene associations with AEs were excluded.

Genetic association studies of AEs

Many AE candidate-gene association studies focused on polymorphisms in genes implicated in asthma or viral pathways. The first genome-wide association study (GWAS) of asthma identified variants at chromosome 17q12-21, with more significant effects in children than adults. The gene-environment (GxE) interactions and genetic variations for chromosome 17q12-21 have been explored concerning AEs.

Studies have identified associations between numerous 17q12-21 variants and the expression of nearby genes in bronchial epithelial cells. Many variants are also located within binding sites for interferon (IFN) regulatory factors, suggestive of effects through antiviral pathways. One GWAS revealed an association between the asthma-related human leucocyte antigen (HLA) DQ Beta 1 (DQB1) and AEs in Hispanic/Latino children and British adults.

Although most AE GWASs have been conducted in Europeans, research efforts have recently widened ethnic diversity and representation. The largest GWAS meta-analysis of Hispanic/Latino children with severe AEs uncovered a significant GWA in LINC03033, a long non-coding RNA (lncRNA) involved in airway remodeling and myofibroblast differentiation.

Lately, a multi-ancestry AE GWAS meta-analysis reported two suggestive variants associated with blood DNA methylation or expression of genes involved in host defense and inflammation. Pharmacogenomic GWAS (PGWAS) of AEs uncovered susceptibility variants for response to long-acting Beta 2 agonists (LABA) and inhaled corticosteroids (ICS).

Several studies reported that genomic regions harboring the loci associated with AEs in children taking ICS are implicated in bronchodilator responsiveness, baseline lung function, and responses to viral infections. Likewise, admixture mapping studies have uncovered genetic variants associated with bronchodilator response, lung function, asthma, and immunoglobulin E (IgE) levels.

Epigenetic and transcriptomic studies of AEs

DNA methylation, non-coding RNAs (ncRNA), and histone modifications are the primary epigenetic mechanisms that synergistically regulate gene expression. One study noted an association of a higher cord blood DNA methylation of the interleukin 2 (IL2) promoter with asthma-related hospitalizations and AEs. Micro RNAs (miRNAs) are small ncRNAs that regulate many cellular processes. Seven studies have evaluated the role of miRNAs in AEs.

One research group reported downregulation of miR-1 in acute-stage asthma, which was significantly more predictive of AEs than asthma-associated cytokines. Another group of researchers recently reviewed AE transcriptomic studies conducted before 2022 and identified distinct AE-associated gene expression signatures involved in immunity and viral/non-viral exacerbations. So far, the only single-cell RNA sequencing study on AEs underscored the implication of intracellular transduction regulators and cytokines in multiple cell types.

Concluding remarks

AEs significantly burden asthmatic individuals, healthcare systems, and society. Although AE prevention is pivotal in clinical practice, risk classification of patients is a daunting task due to the intrinsically heterogeneous biological mechanisms of AEs. Nevertheless, Omics studies have uncovered AE-associated biological processes and genes. Notwithstanding the increasing ethnic diversity in asthma genetic studies, especially for Hispanic populations, extensive genome-wide studies are lacking for African and Asian people.

Despite the progress in genomic studies of AEs, the interaction of different Omic layers in modulating AE risk is unexplored yet, as in many cases, novel findings warrant validation in independent populations. As we advance, multi-ethnic cohorts, improved phenotyping of environmental and clinical features, and integration of multiple Omics layers will help to identify AE biomarkers for precision medicine.

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