Gene-Environment Interactions - A New Clue with Implications for Asthma

PI.: David Schwartz
University of Iowa

Background: Most diseases arise from the complex interaction of underlying genetic susceptibility and environmental exposures that occur over time. Although most people think of environmental exposures in terms of synthetic chemicals, some of our most important exposures are from the natural world. These exposures would include the nutrients in our food, the pathogens normally found in soil and air, and the by-products produced by insects and mites in our homes.

One such exposure is endotoxin. Endotoxins, also known as lipopolysaccharides, are part of the outer membrane of the well wall of Gram-negative bacteria. Inhalation of endotoxin has been implicated in asthma and other respiratory diseases and has been shown to cause chest tightness, wheezing, and difficulty in breathing. Endotoxin-induced asthma is a particular problem in farming occupations that involve handling grain and subsequent exposure to grain dusts. Researchers have recently discovered an important genetic component underlying susceptibility to endotoxin that has implications not only for asthma, but potentially for other airway diseases such as acute lung injury, cystic fibrosis, and pneumonia.

Advance: These investigators studied the response of 83 healthy human participants to increasing concentrations of endotoxin equal to the amount a grain handler or farmer would be exposed to during a normal work-day. The results demonstrated differences in the constriction of the airways between the participants--some exhibited normal constriction while others were affected to a much lesser degree. Further genetic testing led the investigators to attribute the difference in response to mutations in the toll-like receptor- 4 (TLR4) gene. These findings were further substantiated by in vitro experiments conducted on cell cultures obtained from people with the mutation. By adding a normal copy of the TLR4 gene to the cells in culture, the normal cell response to endotoxin was recovered.

Implication: These findings may have future implications on the treatment of asthma and other respiratory diseases. Scientists may be able to capitalize on these findings by designing drugs that will bind to normal TLR4 receptors and thus prevent the bronchoconstriction seen in asthmatics. However, the researchers warn that people with the TLR4 mutation may be more susceptible to blood-borne infections because they may not respond as readily to early signs of infection.

Citation: Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, Frees K, Watt JL, Schwartz DA: TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet. 25: 187-191, 2000.