What is DMAE?

DMAE is the acronym of the R&D project "Integrative omics approach to assess the role of DNA Methylation in Asthma Exacerbations (DMAE)". This project is funded by grant PID2020-116274RB-I00 by the Spanish Ministry of Science, Innovation, and Universities (MICIU/AEI/10.13039/501100011033), being Maria Pino-Yanes the principal investigator.

Asthma is a chronic respiratory disease characterized by reversible airflow obstruction and airway hyperresponsiveness to various stimuli. Despite the asthma symptoms are usually controlled, some patients may develop life-threatening worsening episodes of the disease known as exacerbations. Asthma exacerbations are known to be the major contributor to the global economic and health burden of the disease to patients, caregivers, and society. Both environmental and genetic components have a role in the development of asthma exacerbations, but nowadays, no significant predictive biomarkers are known. Epigenetics, which is considered an intermediate component between these extrinsic and intrinsic factors, encompasses all the processes that regulate gene expression without altering the deoxyribonucleic acid (DNA) sequence. DNA methylation (DNAm) is the most studied epigenetic modification in human diseases, and it has been described to have a role in asthma susceptibility.

However, no prior study has assessed the influence of DNAm in the risk of asthma exacerbations. This project aims to identify changes in DNAm in blood and/or nasal epithelium cells associated with asthma exacerbations in diverse populations, analyze their potential functional effects, and assess whether they are explained by the individual’s genetic variation.

Hypothesis and objectives

The main hypothesis of DMAE is that asthma exacerbations are influenced by differences in DNA methylation patterns in blood and nasal epithelium among individuals. These patterns capture both environmental and genetic factors and have a functional impact on gene expression. The identification of these epigenetic marks could improve the ability to predict an individual's risk of developing asthma exacerbations and have the potential to reveal novel drug targets. Moreover, these changes could be shared among populations or be population-specific.

DMAE aims to examine whether there are cosmopolitan or population-specific DNAm changes in blood and nasal epithelial cells associated with asthma exacerbations that could predict this phenotype, to analyze their functional consequences, and to assess whether they are explained by genetic variation. The specific aims of the project are as follows:

Objective 1. To identify changes in DNA methylation associated with asthma exacerbations and to assess its ability to predict the risk of developing these events in Europeans and multi-ethnic populations.

Objective 2. To study the functional impact of the associated CpG sites and/or differential methylated regions (DMRs).

Objective 3. To assess whether the identified DNA methylation changes associated with asthma exacerbations are explained by genetic variation.

Objectives approach

An epigenome-wide association study (EWAS) analyzing approximately 850,000 CpG sites will be performed in blood and nasal epithelial samples from Europeans, Latin Americans, and African Americans with asthma. Asthma exacerbations will be defined by the following asthma-related events in the past year: emergency visits, hospitalizations, and systemic corticosteroid use. The association between individual CpG sites, differentially methylated regions, and DNAm modules with the presence/absence of asthma exacerbations will be analyzed, adjusting all models by potential confounders. Moreover, changes in DNAm associated with asthma exacerbations will be integrated with information from public datasets to assess their potential implication in biological pathways and to identify drug targets. EWAS results will be followed up for replication in independent populations through targeted next-generation sequencing methylation assays in independent blood and nasal samples in European individuals, as well as with genome-wide methylation microarrays in a subset of Latin American subjects. Validated results will be used to develop a DNA methylation predictive model for asthma exacerbations that will be assessed for classification performance.

Furthermore, the implication of DNAm in gene expression regulation will be investigated in a subset of individuals with available genome-wide transcriptomic data (RNAseq) and publicly available data. Finally, epigenomic and genomic data will be integrated to investigate whether genetic variation explains the changes in DNAm associated with asthma exacerbations.

The results of DMAE will have a significant scientific impact, contributing to increasing our knowledge of the molecular mechanisms underlying asthma exacerbations, improving our prediction of asthma exacerbations, and identifying new potential therapeutic targets for their treatment.