Certain Genetic Mutations Affect Human Response To Environmental Contaminant

The UI investigators determined that mutations in the toll-like receptor-4 (TLR4) gene can cause some people to be less responsive to inhaled endotoxin and less prone to develop an asthma-like response when exposed to this common environmental contaminant. The findings were published in the June issue of Nature Genetics.

"In a fairly large study population of healthy individuals, we found that commonly occurring changes in the genetic sequence of TLR4 can make an individual more likely to be resistant to inhaled endotoxin than those who do not have the mutations," said David A. Schwartz, M.D., UI professor of internal medicine. "However, related studies with mice suggest that people with these mutations of TLR4 who are less responsive to inhaled endotoxin may prove to be more susceptible to systemic effects of endotoxin when they develop a blood-borne infection."

The team studied the response of 83 healthy individuals (31 males, 52 females) to increasing doses of endotoxin that equaled the amount of endotoxin a grain handler or farmer would be exposed to over the course of a normal eight-hour work shift. The participants had no heart or lung disease, no history of cigarette smoking, and no indication of even a tendency toward asthma.

Thirty-one of the participants were hyporesponsive, or less responsive, to the bronchoconstrictive effects of endotoxin, while 52 had normal responses, meaning they experienced chest tightness and other asthma-like symptoms. Seven (22.6 percent) of the 31 hyporesponsive participants had TLR4 mutations. In contrast, only three (5.8 percent) of the 52 normally responding participants had these mutations.

"The individuals who were hyporesponsive did not react to inhaled endotoxin," Schwartz said. "However, individuals with these mutations may prove to be more susceptible to blood-borne infections because they may not respond normally to the early signals of infections."

Schwartz noted that not all people with the mutations were hyporesponsive to endotoxin, and not all people who were hyporesponsive had mutations in TLR4.

"Asthma-like reactions to endotoxin are determined in part by whether a person has the mutation, but it is not the only factor," he said. "This is a complex response that may involve other exposures and certainly involves other genes."

Schwartz said the team also found that the mutation altered the ability of cells in culture to respond to endotoxin. In addition, cells obtained from individuals with the TLR4 mutations could be "rescued" or made to function normally through the addition of a normal copy of the TLR4 gene.

"TLR4 is a cell membrane receptor of endotoxin," Schwartz explained. "The study shows that the mutation results in less expression of this important receptor on the cell surface. This lower receptor density then causes the cell to be less responsive to endotoxin. In effect, there are fewer sites on the cell that can trigger a response to endotoxin."

In addition to treatment implications for asthma and sepsis, the findings could have implications for diseases such as acute lung injury, cystic fibrosis and pneumonia.

Schwartz said the next research steps include studying how the TLR4 receptor works, especially as it relates to airway diseases caused by or exacerbated by endotoxin; using the naturally occurring mutations in TLR4 as a tool to study airway diseases; creating genetically-engineered mice with the human mutation to better understand the basic biology of endotoxin responsiveness; and investigating how the mutation affects other endotoxin-mediated diseases.

Schwartz is also an Iowa City Veterans Affairs Medical Center researcher and staff physician.

The study was supported in part by grants from the federal Department of Veterans Affairs, the National Institute of Environmental Health Sciences, the National Heart, Lung and Blood Institute, and the UI General Clinical Research Centers Program, which is funded by the National Center for Clinical Research.