Gene-gene interaction in asthma: IL4RA and IL13 in a Dutch population withasthma

Asthma is a common respiratory disease that is characterized by variable ai rways obstruction caused by acute and chronic bronchial inflammation; assoc iated phenotypes include bronchial hyperresponsiveness (BHR), elevated tota l serum immunoglobulin E (IgE) levels, and skin tests positive to common al lergens. Binding of interleukin-13 (IL13) or interleukin-4 (IL4) to the IL4 receptor (IL4R) induces the initial response for Th2 lymphocyte polarizati on. 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. We have inve stigated five IL4RA single-nucleotide polymorphisms in a population of Dutc h families ascertained through a proband with asthma. By considering the pr obands and their spouses as an unrelated sample, we observed significant as sociations of atopy and asthma-related phenotypes with several IL4RA polymo rphisms, including S478P and total serum IgE levels (P=.0007). A significan t gene-gene interaction between S478P in IL4RA and the - 1111 promoter vari ation in IL13, previously shown to be associated with BHR (P = .003), was d etected. Individuals with the risk genotype for both genes were at almost f ive times greater risk for the development of asthma compared to individual s with both nonrisk genotypes (P = .0004). These data suggest that variatio ns in IL4RA contribute to elevated total serum IgE levels, and interaction between IL4RA and IL13 markedly increases an individual's susceptibility to asthma.