An international team of researchers from Australia, The Netherlands and the United States sought to develop a method of identifying disease risk for asthma across genetic markers.
The team successfully identified four novel genes (B4GALT3, USMG5, P2RY13, and P2RY14) linked to increased asthma risk, but in order to complete the analysis, the group first created a “gene-based test and software package called EUGENE” to help them identify expression quantitative trait loci (eQTLs) related to asthma risk.
The four novel genes are involved in nucleotide synthesis and activation, and are associated with the regulation of airways and allergens. The genes affect epithelial cells, eosinophils, and neutrophils. Because asthma is a polygenic disease “identifying risk associated variants is important because they could point to genes that were not previously suspected to be involved in disease pathophysiology or that could represent drug targets with greater probability of clinical success,” said Manuel A.R. Ferreira, PhD, with the Berghofer Medical Research Institute in Brisbane Australia.
Identifying variants could help identify specific asthma phenotypes and could thereby assist clinicians in producing effective targeted therapies for specific individuals. According to the study, the research team “tested the association between asthma and 17,190 genes” that had previously been determined by previous studies to have local and distant (referring to chromosomal location of single gene markers) associations with specific gene expressions.
The use of EUGENE testing during this gene wide association study identified 48 genes with asthma risk. A total of 37 of these genes were previously located as genes associated with increased allergic disease risk, but the remaining 11 genes were newly identified as potentially associated with increased asthma risk “not driven by established allergy risk variants.”
Subsequent testing confirmed that four of the genes proved to have novel genetic associations with asthma. Ferreira wrote that although EUGENE can be used to identify genes associated with asthma, it cannot “directly provide” information on disease risk, but rather identifies “genetically determined increases in gene expression levels” which can predict an increase or decrease in disease risk for individuals.
The study discovered that two of the four genes (B4GALT3 and USMG5) were associated with nucleotide synthesis and the remaining two genes (P2RY13 and P2RY14) were linked to nucleotide-dependent cell activation. Ferreira and colleagues hypothesized that these genes may be integral in the “genetic dysregulation of nucleotide signaling,” which contributed to asthma risk increase, particularly eosinophilic asthma risk increase.
The group believed it is likely that these specific genes induce Interleukin 33 release which signals “eosinophilic airway infiltration” increasing inflammation and constricting airways even in the absence of allergen stimulation. The success of the EUGENE process, and the identification of the four novel genes associated with asthma risk suggested that the gene-based testing, which “focuses on documented eQTLs has the potential to identify novel associations.”
Additionally, the observations of the 4 new novel genes suggested that “genetic dysregulation of nucleotide signaling contributes to the risk of asthma (allergic and potentially also nonallergic) and other related conditions.”
The new information about these specific genes and their connections to airway inflammation associated with asthma could potentially allow researchers to not only identify increased risk in individuals, but to also target therapies based on specific gene expressions. Further testing is needed to confirm the study’s findings.
The article “Gene-based Analysis of Regulatory Variants Identifies 4 Putative Novel Asthma Risk Genes related to Nucleotide Synthesis and Signaling” was published in the April 2017 issue of The Journal of Allergy and Clinical Immunology.