Asthma is a chronic condition that affects 25 million people in the United States. Having a mother with asthma is an important risk factor and a new study may explain why. A team of researchers have found striking epigenetic differences in the airway cells of patients with asthma who have asthmatic mothers, compared to patients whose mothers never had asthma. The research was published in Proceedings of the National Academy of Sciences.

The research team have spent years examining genetic influences that contribute to the development of asthma, including epigenetic factors. Epigenetics refers to changes in how genes are expressed that are not directed by changes or mutations in the DNA sequence itself. Instead, gene activity can be turned on or off by the attachment of small chemical structures such as methyl groups to DNA. Many environmental factors are known to impact DNA methylation patterns, including the in-utero environment.

In the study, the team found different DNA methylation patterns in epithelial cells of the lower airways of asthmatic adults with asthmatic mothers compared to those whose mothers did not have asthma.

“The methylation patterns in those with asthmatic mothers were tied to reduced expression of genes in immune-related pathways” said the first author.

These immune-related pathways are associated with impaired T cell signaling, a type of adaptive immune cell involved in fighting off infections, including pathways linked to impaired immune responses to viruses and bacteria. Clinically, there is a severe type of asthma, referred to as type 2-low asthma, that is defined by the lack of responsiveness to standard corticosteroid treatments, which suppresses inflammatory processes.

“This subtype of asthma is particularly difficult to treat,” said the senior author. “Our results suggest that an underlying cause is due to impaired immune responses, potentially explaining lack of therapeutic response to corticosteroids and suggesting alternative pathways to target as therapies for this group of patients.”

One important element in this study is that it was conducted in a diverse population. Participants of the study were patients from the UChicago Medicine asthma clinics. Many live on the South Side, where asthma rates are especially high.

“Having representation of diverse ancestry and sociocultural factors is important in research, as it tells us these findings hold true across various populations,” said the author. There are significant disparities in asthma rates, which further emphasizes the need for diversity in asthma research.

The study was conducted with cells taken from adult patients, but excitingly, the results were replicated in airway epithelial cells taken from an independent group of children. Researchers believe that the observed epigenetic modifications in the asthmatic patients likely occurred during pregnancy, and exposure to the asthmatic mother’s in-utero environment shaped their potential to develop asthma later in life.

“The fact that these results were replicated in a separate cohort of children supports the notion that these modifications are present long before adulthood,” said the author.

More research is needed to determine the timeline of these changes and their effects on asthma. The team is working on a longitudinal study in infants to further examine these temporal effects.

https://www.pnas.org/doi/abs/10.1073/pnas.2116467119