NIEHS-funded scientists have discovered a mucus-regulating gene that may have important implications for asthma severity. The research, led by Samir Kelada, Ph.D., of the University of North Carolina at Chapel Hill (UNC), was published in the October issue of the journal Genetics. Lead author Lauren Donoghue was a postbaccalaureate fellow at NIEHS and is now pursuing her Ph.D. at UNC.
The lungs produce mucus as a key defense against pollutants and allergens, but too much mucus results in airway obstruction. The research team identified a gene called Bpifb1 as a novel regulator of a protein called MUC5B. MUC5B is a critical protein in mucus produced during life-threatening asthma attacks, as well as in other respiratory diseases like chronic obstructive pulmonary disease and cystic fibrosis.
There are many genes known to affect asthma, but those do not affect the baseline levels of mucus that different people produce. “Mucus production is an important aspect of asthma attacks,” said Kelada. “Identifying the Bpifb1 gene may give us another treatment target to pursue.”
Mice help in asthma gene discovery
Disease severity varies widely among asthmatics, and Kelada says this is in part due to genetics. To mimic the range of human asthmatic responses in the laboratory, his research team used special mice, bred using the Collaborative Cross framework. These mice have a diverse but carefully tracked genetic makeup so they can be used for experiments to test genetic variation.
Kelada’s team triggered inflammation and mucus production in 154 Collaborative Cross mice using dust mite proteins — a common allergy trigger. As expected, the mice responded with a range of mucus production levels.
The researchers compared the mucus proteins produced and the genetic makeup, or genotype, of the mice. They focused on genetic differences potentially related to two mucus proteins in particular, MUC5AC and MUC5B. The team found that genetic differences were indeed driving the variation in the production of these proteins.
For MUC5B protein levels, the results were especially striking. Bpifb1 was identified as a gene responsible for the amount of MUC5B in airway mucus. To confirm their finding, Kelada and his team eliminated the Bpifb1 gene in the mice and observed that it had a role in regulating the MUC5B protein in mucus.
For MUC5AC protein levels, no one gene stood out, but the researchers identified four genes for further study.
Adding ozone exposure to the mix
In addition to confirming similar effects in people, the UNC team will also test how the asthmatic response to ozone, a common air pollutant, may change due to genetic variation. In 2015, Kelada received an NIEHS Outstanding New Environmental Scientist (ONES) award (see sidebar) to study how genes contribute to asthmatic responses to allergens and ozone.
“The genetics of asthma are really complicated, especially when you add the variation in people’s response to environmental factors,” said Kimberly McAllister, Ph.D., of the NIEHS Genes, Environment, and Health Branch, who oversees the ONES award. “This study helps tease out this complexity and identify subpopulations that may be especially susceptible, so we can ultimately improve treatment and prevention.”
Citation: Donoghue LJ, Livraghi-Butrico A, McFadden KM, Thomas JM, Chen G, Grubb BR, O'Neal WK, Boucher RC, Kelada SNP. 2017. Identification of trans protein QTL for secreted airway mucins in mice and a causal role for Bpifb1. Genetics 207(2):801–812.
(Virginia Guidry, Ph.D., is a technical writer and public information specialist in the NIEHS Office of Communications and Public Liaison and a regular contributor to the Environmental Factor.)