Enabling a Precision Approach to Asthma

As the COVID-19 pandemic threatens to stretch into its third year, most of us have grown acutely aware of our breathing, with even slight difficulties in respiration raising alarm bells. But for people with asthma, such awareness has been a way of life.

Afflicting some 300 million people worldwide1, asthma is the most common chronic condition of the lungs. But in truth, asthma encompasses many lung disorders, each with a distinct set of clinical features. Recognising this diversity, clinicians and researchers have further classified asthma into subtypes according to the different ways the disease manifests, or phenotype, and the different pathways that give rise to it, or endotype. Once classified, treatments can be fine-tuned accordingly, increasing the chance ofbetter outcomes. Precision medicine pushes this classification of asthma one step further by also looking at genetic information, while accounting for medical history and environmental exposures. One such genetic factor is the presence of single-nucleotide polymorphisms (SNPs), common variations found in DNA sequences that may demarcate regions of disease relevance.

The Unusual Suspects

“Identifying the genes, disease-associated SNPs are associated helps us understand the mechanism and potential interventions for altering disease,” said Dr Anand Kumar Andiappan, a Principal Investigator who studies biomarkers for allergies, infection and respiratory disorders at A*STAR’s  Singapore Immunology Network (SIgN).

In a letter2 published in The Journal of Allergy and Clinical Immunology, Andiappan reported the association between a SNP called rs2427837 and the FCER1A gene, which codes for receptors for IgE, an antibody that mediates allergic responses in asthma and increases immune reactivity in the airways. To clarify the role of rs2427837 in asthma severity and potentially find a candidate gene affecting asthma risk, Andiappan and his colleagues looked at mRNA data from more than 30,000 blood samples from 30 different cohorts worldwide. They found a strong and consistent correlation between the rs2427837 SNP and expression of the FCER1A gene.

“We were able to identify the candidate gene, which may even be a causal gene, affecting asthma risk,” Andiappan said. To better understand the SNP’s functional consequences, the research team next looked for the specific cell types most affected by rs2427837. Analysing the blood samples at the single-cell level, the team looked for cell types that showed increases of FCER1A protein levels in relation to rs2427837.

Initially, they expected to find their answer in basophils, a kind of immune cell that increases in asthmatic airways and allergies. To their surprise, rs2427837 had no impact on FCER1A expression in basophils. Instead, the SNP exerted its impact on two other cell types that weren’t typically implicated in asthma: monocytes, which give rise to immune cells that attack invading microbes, and plasmacytoid dendritic cells (pDCs), immune cells which are chiefly involved in the body’s anti-virus response.

“We believe this has not been reported before although the role of monocytes and pDCs in asthma has been suggested,” said Andiappan. “Hence, our future work should look at the immune regulation in these cell types.”

Asthma’s Balancing Act

Aside from finding these two new potential players in asthma, the team also discovered that the rs2427837 SNP affected monocytes and pDCs differently depending on their genotype. “Genotype refers to the combination of alleles at a particular position on the DNA,” Andiappan explained. “When there is a SNP at that position, there are three possible genotype combinations.” In the case of rs2427837, these are the AA, AG, and GG genotypes. Of the three genotypes, AA had the strongest effect on monocytes, leading to exceptionally high levels of the FCER1A protein. In contrast, for pDCs: the mere presence of the G allele correlated with heightened expression of FCER1A.

According to Andiappan, the fact that the SNP affects these cells in different ways reveals the importance of a balanced immune response. If FCER1A expression is balanced between monocytes and pDCs, as in the case of the AG genotype, then immune response is well-regulated, and asthma is kept at bay. However, when GG dominates, FCER1A expression jumps in pDCs, and the body enters a pro-inflammatory state, leading to the typical symptoms of asthma, including constricted airways and sustained chronic inflammation. Clarifying the role of the rs2427837 SNP and FCER1A in asthma—and how they interact with each other to give rise to the disease—is a big step toward targeted therapy, but there is still much work left to do.

“Our findings highlight the intricacy of varying FCER1A levels in different immune cells and their dependency on the genotype of the individual,” Andiappan said, adding that targeting FCER1A needs to be done at an individual level, taking account of a patient’s genetic, disease and physical profiles. While current medical precision still isn’t at that level, Andiappan is hopeful. As medicine moves away from the traditional one-size-fits-all therapies, FCER1A may yet open the doors to treating asthma with precision.

References:

1. Dharmage, S.C., Perret, J.L., Custovic, A. Epidemiology of Asthma in Children and Adults. Front Pediatr 7, 246 (2019).

2. Andiappan, A.K., Puan, K.J., Lee, B., Yeow, P.T., Yusof, N., Merid, S.K., et al. Inverse association of FCER1A allergy variant in monocytes and plasmacytoid dendritic cells. J Allergy Clin Immunol 147(4), 1510-1513 (2021).