St. Louis, Dec. 11, 1997 -- Allergic diseases are among the major causes of illness and disability in the United States, affecting as many as 40 to 50 million Americans. Researchers have known for some time that allergies have a genetic link, but information about which genes are responsible has been limited. Now, scientists at Washington University School of Medicine in St. Louis have identified a genetic mutation that appears to make people more susceptible to allergies.
"This is one of the strongest associations so far between any one particular gene and allergies," said Talal A. Chatila, M.D., associate professor of pediatrics and senior author of the study, which appears in today's issue of The New England Journal of Medicine. "We have found that if you have this mutation, you are 10 times more likely to be allergic."
In the short term, this finding will help advance studies to identify highly susceptible individuals, Chatila said. The discovery also could lead to more targeted medications for allergies.
The immune system normally defends the body against invading agents such as bacteria and viruses. But it sometimes confuses other foreign substances such as dust mites and certain foods with harmful intruders. When allergic people first come into contact with such allergens, their immune systems mobilize to respond. First, they generate large amounts of a type of antibody -- a disease-fighting protein -- called immunoglobin E (IgE). The IgE molecules then attach themselves to mast cells in tissues and basophils in blood. When an allergen encounters the IgE, it attaches to the antibody like a key fitting into a lock. This signal tells the mast cell or basophil to release, and in some cases to produce, powerful inflammatory chemicals like histamine, prostaglandins and leukotrienes. The production of these chemicals in various parts of the body, such as the respiratory system, initiates an allergic reaction such as seen in asthma. IgE is key to this process because it triggers the chain of events that leads to symptoms.
Another key protein is interleukin-4, which induces immune cells to make IgE. Chatila and his colleagues studied the receptor for interleukin-4. Using techniques called single-strand polymorphism analysis and DNA sequencing, they searched for variations in the gene for one of the subunits of the interleukin-4 receptor. Then they determined how common the variant was in patients with severe allergic inflammatory disorders and healthy adults.
One variant occurred at high frequency in patients with allergic inflammatory disease and in adults with various allergies but at a low frequency in adults with no allergies. This genetic alteration occured at the tail end of the interleukin-4 receptor, Chatila and his colleagues discovered. The consequence, they showed, was that the receptor becomes hyperesponsive when stimulated with interleukin-4.
"This mutation makes the receptor function better, so it signals the cells to make IgE antibodies more effectively than it would have done otherwise," Chatila said. "Therefore, people with this altered receptor gene are more likely to develop allergies."
Environmental factors also play a role in whether an individual develops allergies. Previous studies have established that avoiding particular allergens in childhood substantially decreases the risk. Breast feeding also helps guard a child against allergies.
Identifying the altered receptor gene could greatly aid studies of allergic reactions. "This finding will help us identify individuals at high risk of developing allergies and evaluate intervention strategies aimed at protecting these individuals from developing allergic disorders," Chatila said.
The genetic finding also could help researchers develop better medications to treat allergies. Because the identified target is unique, Chatila said, drugs could be developed that are more specific and have fewer side effects.
In future studies, Chatila and colleagues will study other mutations along the pathway between the activation of the interleukin-4 receptor and the production of IgE to find out what happens if a person has more than one mutation. They hope to determine if different combinations of mutations predispose individuals to specific allergies.
This discovery is an important first step. "We know that the process by which some people develop allergies is not random but is genetically determined," Chatila said. "This study helps clarify the basis for this genetic predisposition."
In addition to Chatila, other authors of this study are lead author Gurjit K. Hershey, M.D., Ph.D., now at the University of Cincinnati School of Medicine, Michael F. Friedrich, now at Loyola University School of Medicine, and Matthew L. Thomas, Ph.D., and Laura A. Esswein, M.D., Washington University School of Medicine.
Journal
New England Journal of Medicine