CONTACT: BECKY SOGLIN
2130 Medical Laboratories
Iowa City IA 52242
(319) 335-6660; fax (319) 335-8034
Release: May 31, 2000
UI study: mutations in a gene affect human response to environmental contaminant
IOWA CITY, Iowa -- University of Iowa Health Care researchers have found
the first genetic evidence that mutations to a certain gene are associated
with differences in the human response to inhaled endotoxin, a contaminant
commonly found in agricultural dust, air pollution and household dust.
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
"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
"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
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
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
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