Investigators found that asthma symptom severity results from the interaction of genetic susceptibility to pollution together with the severity of pollution exposure.
Stavros Garantziotis, MD
Asthma patients with specific genetic profiles were found to have more severe asthmatic symptoms from the air pollution of nearby roadway traffic, in a novel investigation illustrating how precision medicine may be able to incorporate both genetic and environmental factors.
The study conducted by investigators at the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), and the Children's Environmental Health Initiative drew on the genotype, address, and asthma diagnosis and exacerbation data from the Environmental Polymorphisms Registry.
"This study set out to test, as a proof of principle, the ability to use refined population analysis of gene-environment interactions to create personalized predictions for the activity of a complex disease," wrote co-lead author Stavros Garantziotis, MD, medical director of NIEHS Clinical Research Unit, and colleagues.
The first challenge faced by the investigators was to identify a particular genotype that could underlie susceptibility to asthma, characterizing the individual genes and single nucleotide polymorphisms (SNPs) responsible for the increased risk.
Garantziotis and co-lead author Shepherd Schurman, MD, associate medical director of NIEHS Clinical Research Unit explained in a statement about the study released by the NIEHS that physiological and clinical effects of an SNP are usually discerned by studying it in isolation from other genes and SNPs.
In this study, however, they were interested in learning whether different combinations of SNPs, along with pollution exposure, could worsen asthmatic symptoms that arose through inflammation.
The investigators were guided by earlier evidence that air pollutant activation of innate immunity includes provoking response of genes in the toll-like receptor 4 (TLR4) inflammatory pathway, and that SNPs which interfere with TLR4 functions are associated with asthma. Garantziotis, Schurman and colleagues then examined 3 genes in the TLR4 complex, with 4 SNPs selected for their relatively high minor allele frequency (MAF) and for evidence from previous studies that relate the minor alleles to particular clinical manifestations.
Based on the evidence of the clinical implications of particular SNP combinations, 2704 study participants were categorized into 3 groups: as hyper-responders, who were likely to be sensitive to air pollution and develop inflammation; hypo-responders less likely to develop inflammation; and a group whose genetic profiles suggested response in between these, and classified as "neither-responders.” These genotyped participants were then geocoded, and grouped by whether or not their residence was within 250 meters of a major road.
The investigators reported finding the odds ratio (OR) of an asthma diagnosis among hyper-responders living within 250 meters of a major road was 2.37 (95% CI; 0.97 - 6.01) compared to a reference group. Hypo-responders living further than 250 meters from a major road had lower odds of reporting activity limitations, sleeplessness, and any asthma exacerbation compared to neither-responders.
The findings suggest that asthma symptom severity results from the interaction of genetic susceptibility to pollution together with the severity of pollution exposure, Garantziotis told MD Magazine®.
"Patients who had genetic variations that made them especially responsive to pollution,” Garantzios said, “and also lived close to a pollution source—a major roadway—had the most symptoms, while the other extreme—patients who had the least genetic responsiveness to pollution and also lived far from major roadways—had the least symptoms.”
This study suggests the possibility of creating gene analysis panels that are paired with the exposures to identify particularly vulnerable individuals for environmental remediation, he noted.
"Based on this research, we could propose that hyper-responders, who are exposed to traffic pollution, receive air purification intervention, such as HEPA filters, for their home," Garantziotis said in a statement.
Co-author Marie Lynn Miranda, PhD, Howard R. Hughes Provost and professor of statistics at Rice University, also commented on the portent of this study with MD Mag.
"This work provides important first steps for understanding mechanisms by which genetic and environmental factors shape respiratory outcomes,” Miranda said. “We hope eventually to illuminate potential precision medicine interventions, as well as provide policy guidance on the regulation of air pollution.”
The study, “Toll-like Receptor 4 Pathway Polymorphisms Interact with Pollution to Influence Asthma Diagnosis and Severity,” was published online in Scientific Reports.