Scientists identify genes linking air pollution to severe asthma

For many people with asthma, air-quality advisories are harbingers of worsening symptoms. But for reasons science has struggled to explain, the extent to which pollution exacerbates asthma varies widely from person to person.

In a study published today in eBioMedicine, researchers from the University of Pittsburgh School of Public Health, in collaboration with the Severe Asthma Research Program (SARP), identified biological pathways that begin to uncover this mystery, showing how air-pollution exposure interacts with a person's genes. The study-which is among the largest and most comprehensive of its kind to date-could eventually lead to new avenues for asthma-drug development, as well as potential new biomarkers and public-health interventions targeted to those who are most vulnerable to pollution-exacerbated asthma.

Using data from nearly 1,000 adults with asthma across the country who had enrolled in SARP, the analysis included a combination of whole genome sequencing, air pollution exposure data and gene-expression profiling. Among the thousands of genes in the human genome, the team focused on about 450 genes that control oxidative stress, a process in which highly reactive molecules can damage cells and tissues.

"Those stresses on cells can translate into serious physiologic effects, like worsening lung function or asthma exacerbations," said Sally Wenzel, M.D., corresponding author, chair of Pitt Public Health's Department of Environmental and Occupational Health and director of Pitt's Asthma and Environmental Lung Health Institute at UPMC, who co-led the study with Shuangjia Xue, a recent graduate of the department's Ph.D. program.

The team focused on how these genes interacted with the environmental stress of exposure to fine particulate matter known as PM2.5. These microscopic particles, with a diameter less than that of a human hair (less than 2.5 microns), are small enough to penetrate deep into the lungs and are widely considered one of the most harmful components of air pollution.

A clear relationship emerged.

"In these individuals who were living with asthma, the higher their exposure to this particulate matter, the lower their lung function overall," said Wenzel, adding that the study focused on people who were already living with asthma, rather than in the process of developing the disease.

The study was the first of its kind to use human airway samples in an analysis of gene transcription-that is, how DNA is converted into RNA, which in turn directs cells to produce proteins. "Genes lay out who we could be, but the RNA, and the proteins they transcribe, are what make us who we are," Wenzel said. The airway epithelial cell samples were collected through bronchial brushings in a subset of about 200 study participants. The data showed how gene activity changed in response to pollution exposure.

The researchers found that the most vulnerable patients carried variants in seven oxidative stress–related genes that shape how the body responds to cellular damage from pollution. These genetic variants appear to influence how airway cells respond to the PM2.5 exposure, with some variants enhancing protection from PM2.5, while others appear to worsen the damage.

Individuals with less common variants in two specific genes, called OXSR1 and PXDN, had disproportionately worse lung function due to lower protective RNA responses to pollution. Those with a specific variant in another gene, called TPO, had worse lung function, as well, but for them, it was due to stronger RNA responses.

The molecular pathways described in the study could point to targets for new therapies-and open the door to much more.

"You could imagine a simple test for a panel of genes that could be used to flag someone as highly susceptible to the effects of pollution," said Wenzel. That kind of approach could enable both precision medicine-tailoring care to an individual-and precision public health-targeting interventions to specific populations most likely to benefit.

The team's next steps include digging deeper into the pathways identified in this study and testing whether targeted interventions, ranging from behavioral changes to targeted anti-oxidant therapies, can blunt the harmful effects of pollution in high-risk individuals.

We're already exploring some of these pathways. Ultimately, while reducing the amount of pollution remains the most effective approach, the findings from our study suggest we could develop interventions specific to at-risk people that would lessen the impact of pollution."

Sally Wenzel, M.D., corresponding author, chair of Pitt Public Health's Department of Environmental and Occupational Health