Wheezing, shortness of breath, and coughing fits—for millions living with asthma, it can be difficult to pinpoint the environmental factors triggering these attacks. Likewise, what makes some people more susceptible to developing this chronic respiratory disease is also largely unknown. While asthma is known to have a strong genetic basis, scientists are still trying to make sense of the complex gene networks involved.
Anand Kumar Andiappan, Principal Investigator at A*STAR’s Singapore Immunology Network (SIgN), and international collaborators are coming together to unravel asthma’s genetic mysteries. The researchers were particularly interested in single nucleotide polymorphisms (SNPs), a common genetic variation that involves the substitution of a single base pair in the DNA sequence.
In search of SNP signatures associated with allergen sensitivities, the team analyzed large databases of genetic and clinical data collected from over 31,000 people worldwide. This extensive search scope was critical for getting conclusive answers.
“The impact of SNPs on the function of immune cells are usually subtle and larger sample sizes are needed to ensure statistical significance,” explained Andiappan. “Once we find these significant associations, we can perform targeted functional experiments in smaller cohorts.”
The team identified a connection between an SNP known as rs2427837 and the FCER1A gene that codes for receptors for allergy-inducing IgE antibodies. Next, they mapped the rs2427837 gene variations onto immune cell functions using flow cytometry, a technique used to detect and measure the physical and chemical characteristics of a population of cells or particles.
Interestingly, rs2427837 affected two key immune cell populations: white blood cells called monocytes and rare bone marrow-derived cells known as plasmacytoid dendritic cells (pDCs). Both these cell types had previously been identified as mediators of allergic responses in the lungs.
Andiappan and colleagues found that SNPs dictated distinct expression levels of IgE receptors on monocytes and pDCs. For instance, rs2427837—a variation comprising of two guanine (GG) bases, one of the four types of bases found in DNA—resulted in an increased expression of IgE receptors on pDCs than on monocytes. However, those with the adenine-guanine (AG) variation had relatively equal IgE receptor expression levels between the two immune cells.
Taken altogether, the team’s findings form the basis of a novel framework for leveraging genomic data to predict asthma susceptibility. “Those with the GG variation are significantly more likely to develop asthma, while individuals with the AG variation are in the lower-risk group,” explained Andiappan.
Moving forward, the researchers are looking to collect further clinical data in hopes of unlocking new therapeutic targets for asthma and allergies. “We are now working with clinicians to understand if children with severe allergies have a high-risk genotype for rs2427837,” said Andiappan.
The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network (SIgN).