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fact
sheet
Atopic
Asthma and Interleukin-4
Bernadette deGuzman, William Duck, Angela Myrick, Suzanne Proctor, Nupur
Sashti, and Mary Beth Weber (Emory University School of Public Health,
Dept. of Epidemiology)
print version
Published
June, 2001
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IL-4
Gene |
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The
gene for Interleukin-4 (IL-4) is located on chromosome 5 at position |
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q31.
IL-4 is a cytokine secreted by TH-2 cells that stimulates the
production of IgE and induces eosinophil-mediated attacks against
helminthic infections and allergens. |
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Gene Variants |
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Of
the five variants in the promoter region, four are rare. No association
with atopy or asthma has been found for two of the four rare variants.
The most common variant, C590T, has been associated with higher IgE
levels in Japanese and U.S. populations.
The prevalence varies in populations, with the T allele as common
as 79% in Asian populations and as low as 18% in U.S. Caucasians.
Overall, little is known about the prevalence of gene variants
within various populations.
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| Disease
Burden |
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Polymorphisms
in the promoter and the intron 2 regions of the IL-4 gene have been
associated with a variety of allergic conditions, including atopy, eczema,
rhinitis and asthma (both atopic and nonatopic). Although published
research addressing the role of IL-4 allelic variants in the former three
conditions is substantial, fewer than ten epidemiologic studies have
examined the link between IL-4 and asthma.
Promoter. A population-based case-control study of Japanese school
children found that children with asthma were 2.5 times more likely as
their nonasthmatic siblings and twice as likely as nonasthmatic population
controls to carry at least one copy of the T allele.
A Kuwait hospital-based study reported similar findings.
A subsequent case-control study of Canadian infants at high risk
for asthma found infants that were diagnosed with “probable asthma” at
12 months were 4.1 times more likely than their peer controls to carry the
T promoter allele. Another
Canadian study showed a significant link of the IL-4 590T allele to asthma
severity. Notably, the source
populations differed in this study, with cases selected from Australia,
New Zealand, and Vancouver. Controls
were drawn exclusively from study participants in Vancouver.
One U.S. study significantly linked the TT genotype to reduced FEV1
in whites.
Intron
2. A case-control study in Tunisia reported a significant
increase in prevalence of the A1/A3 genotype in people with asthma and
further linked the A1 allele to a moderate to severe phenotype.
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| Gene-Gene
Interactions |
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Because
IL-4 carries out its biological effects through binding to the IL-4
receptor complex, interactions between IL-4 and IL-4R polymorphisms were
investigated. Of the five
receptor-site polymorphisms that have been linked to an altered gene
product, only a few have been studied extensively.
One study looking at the effect of IL-4, IL-4Ra,
and FCERIB genes on asthma severity did not detect a significant
interaction between IL-4*C590T and IL-4Ra*Q576R
polymorphisms when looking at asthma severity.
Future studies may include genes encoding cytokines or cytokine
promoters (IL-4, IL-5, IL-13), genes encoding T cells, IgE, and cytokine
receptors (IL-4R, JCR, and FceRI1)
and genes that influence bronchial responsiveness (B-AR,
lipoxygenase gene).
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Gene-Environment
Interactions
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Few
studies have looked directly at interactions between genes and
environment; however, the basic mechanism underlying the development of
atopic asthma is similar for all environmental exposures. Factors that led
to a polarization towards a TH-2 phenotype in young children include
dietary factors such as drinking cow or soy milk rather than breast milk,
maternal smoking, birth during high pollen counts, and lack of exposure to
microbial and viral infections. Infants
with many older siblings are theoretically exposed to more infections,
which polarize their immune systems toward a TH-1 phenotype and thus
protects them against developing allergies, including asthma, later in
life. Exposure to dust mite
and cockroach allergens mount a humeral response, which can result in
asthma attack. Other
environmental factors such as smog, caused by such factors as diesel and
sulfur dioxide particles, are also linked to the increased incidence of
asthma attacks. These
particles bind to airway mucosa and act on aryl hydrolase receptors,
thereby increasing IL-4 levels and mounting an IgE-specific response.
Additionally, some researchers have studied the interaction between
antibiotics and IL-4 expression. In
one study, B-lactamsms
and cepholasporins increases IL-4 production.
Other studies have shown antibiotics to suppress levels of IL-4.
Further research is needed to clarify the possible mechanisms
between antibiotics and IL-4 levels.
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| Laboratory
Tests
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Clinically,
IL-4 allelic variants can be identified using polymerase chain reaction;
however, no laboratory tests are available to the general public for
diagnostic purposes.
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| Population
Testing |
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No
population-based testing exists for any genetic polymorphisms related to
asthma. The public use of
such a test is not practical because: 1) asthma is a polygenic condition,
and the gene-disease relation is still poorly understood; 2) no preventive
intervention exists. Tests
could be effective measures for assessing the efficiency of treatment
options as they relate to various asthma gene polymorphisms.
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| References |
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De
Swert, L.F.A. Risk factors for allergy. Eur
J Pediat 1999; 158; 89-94.
Mackay,
I., Rosen, F. Allergy and allergic diseases.
N Engl J Med 2001; 344; 30-37.
Sanford
AJ, Chagani T, Zhu S, Weir T, Bai T, Spinelli J, et al.
Polymorphisms in the IL-4, IL-4Ra, and FCERIB genes and asthma severity.
J. Allergy Clin Immunol 2000: 106;
135-140.
Shirakawa,
T., Deichmann, K., Izuhara, K., Mao, X., Adra, C., Hopkin, J. Atopy and asthma:
genetic variants of IL-4 and IL-13 signaling.
Immunol Today 2000; 60
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Web sites |
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Allergy
and Asthma Information Online
National
Asthma Campaign
American
Lung Association
Asthma
Gene Database
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