Genetic Risk for Allergy and Asthma Affects 20 to 40 Percent of Population
As pediatricians and family physicians battle the rising incidence of asthma and allergies among their patients, ongoing research at the Cincinnati Children's Division of Allergy and Immunology is revealing new knowledge about the genetic components of the disease, how humans are affected, and what new treatments and preventive measures might be possible.
A new study led by Gurjit Khurana Hershey, MD, PhD, reinforces previous findings that allergies and asthma are largely genetic disorders that also can be influenced by environment. The study found that the presence of two common genetic polymorphisms of the IL-4 receptor α gene contributes to the development of asthma. These polymorphisms are very common and occur in 20 to 40 percent of the population. Thus, physicians are likely to have patients who have these polymorphisms. Some of these individuals may already have asthma, while others are at risk of developing it, even if they are not yet symptomatic.
The IL-4Rα gene is known to be associated with asthma. IL-4Rα is part of the receptor for the products of both the IL-4 and IL-13 genes, thus it is critical for the action of IL-4 and IL-13. These two genes have been proven essential in the development of allergies in human and animal studies; IL-4 is also essential for T-cell differentiation. "The IL-4Rα gene itself has eight known polymorphisms, and two of them occur commonly, in 20 to 40 percent of the population. We wanted to determine the effect those common polymorphisms might have on asthma and allergy," Dr. Hershey explains.
Two Gene Variations Important
In the laboratory, researchers created four variations on IL-4Rα: the wild type, or the gene as it occurs normally; one with the polymorphism R576; another with the polymorphism V75; and a fourth with a combination of the two, V75R576. When cells expressing each of the four types were exposed to IL-4, the cells with both polymorphisms produced a response three times higher than the other types of cells. "From these findings, we hypothesized that people with both polymorphisms are much more likely to have asthma and allergies," Dr. Hershey says.
Strikingly, the laboratory study also revealed that both polymorphisms must be present to increase the risk; either one alone is not as strong as both variations appearing together. "There is something different about the receptor itself when both polymorphisms are present," Dr. Hershey explains.
These findings were confirmed in a study of 200 asthmatic individuals and 65 nonatopic individuals in a control group. Genotyping revealed that the V75R576 combined polymorphism was significantly associated with atopic asthma in the group of patients with asthma. As in the laboratory, the combination was more strongly associated with asthma than either variation by itself.
This study is part of the comprehensive approach to asthma and allergy research which has merited Cincinnati Children's millions of dollars in funding from the National Institutes of Health and other agencies. Researchers are studying not only the molecular and genetic bases of asthma, but also the role of mediators, and employing mouse models to gain a better understanding of how the disease functions.
Identifying Multiple Asthma Genes
"We are working to find the combination of genes that produces asthma. In patients with asthma, we're using DNA chip arrays to determine which genes are turned on so that we can identify other genes we should be studying," Dr. Hershey says.
Currently, Dr. Hershey is conducting extensive studies focused on gene and environment interactions in the development of childhood allergies and asthma. "The question we're asking is, can we genotype you as an infant and predict that you'll get allergies? If we can make that prediction, then we should be able to intervene," she says.
"We're planning additional studies to determine if we can prevent or change the course of allergies or asthma before children with the genetic predisposition show any symptoms. We've shown that if you have two copies of the IL-4Rα polymorphisms, you're more likely to get severe asthma. I believe that a genetic test for asthma will be developed in the next 10 years. Physicians will be able to better customize their treatment if they know their patient is genetically predisposed to develop severe asthma."
This study was published in The Journal of Immunology (169[3]:1604-1610, 2002 August 1) and was supported by grants from the National Institutes of Health and the March of Dimes.
