Gene-gene interaction in asthma: IL4RA and IL13 in a Dutch population with asthma.
Asthma is a common respiratory disease that is characterized by variable airways obstruction caused by acute and chronic bronchial inflammation; associated phenotypes include bronchial hyperresponsiveness (BHR), elevated total serum immunoglobulin E (IgE) levels, and skin tests positive to common allergens. Binding of interleukin-13 (IL13) or interleukin-4 (IL4) to the IL4 receptor (IL4R) induces the initial response for Th2 lymphocyte polarization. Both IL13 and IL4 are produced by Th2 cells and are capable of inducing isotype class-switching of B-cells to produce IgE after allergen exposure. These cytokines also share a common receptor component, IL4R alpha. We have investigated five IL4RA single-nucleotide polymorphisms in a population of Dutch families ascertained through a proband with asthma. By considering the probands and their spouses as an unrelated sample, we observed significant associations of atopy and asthma-related phenotypes with several IL4RA polymorphisms, including S478P and total serum IgE levels (P=.0007). A significant gene-gene interaction between S478P in IL4RA and the -1111 promoter variation in IL13, previously shown to be associated with BHR (P=.003), was detected. Individuals with the risk genotype for both genes were at almost five times greater risk for the development of asthma compared to individuals with both non-risk genotypes (P=.0004). These data suggest that variations in IL4RA contribute to elevated total serum IgE levels, and interaction between IL4RA and IL13 markedly increases an individual's susceptibility to asthma.
Howard
Timothy D
TD
Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Koppelman
Gerard H
GH
Xu
Jianfeng
J
Zheng
Siqun L
SL
Postma
Dirkje S
DS
Meyers
Deborah A
DA
Bleecker
Eugene R
ER
D001249:Asthma / Q000235:genetics* / Q000276:immunology; D004843:Epistasis, Genetic; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D018793:Interleukin-13 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D019948:Receptors, Interleukin-4 / Q000235:genetics*; D012044:Regression Analysis
D018793:Interleukin-13; D019948:Receptors, Interleukin-4; D007073:Immunoglobulin E