Gene-Gene interaction increases susceptibility to asthma: IL4Ra and IL13 polymorphisms in an asthmatic Dutch population. T.D. Howard¹, G.H. Koppelman^2,3, J. Xu¹, S.L. Zheng¹, D.S. Postma², D.A. Meyers¹, E.R. Bleecker¹. 1) Center for Human Genomics, Wake Forest Univ Sch of Med, Winston-Salem, NC; 2) Department of Pulm, University Hospital, Groningen, the Netherlands; 3) Dept of Pulm, Rehab Beatrixoord, Haren, the Netherlands.
   Asthma is a common respiratory disease characterized by variable airways obstruction caused by acute and chronic bronchial inflammation. Clinical findings in asthma include bronchial hyperresponsiveness and allergic responses, demonstrated by elevated total serum IgE levels and positive skin tests to common allergens. These closely associated phenotypes have been shown to have a strong genetic component. Binding of IL4 to the IL4 receptor (IL4R) induces the initial response for Th2 polarization. IL4 and IL13 are both 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, IL4Ra, which is a potential biological candidate gene for asthma and atopy. We have investigated five IL4Ra single-nucleotide polymorphisms in a well-characterized population of Dutch families ascertained through a proband with asthma. Using the probands and their spouses from this population in a case-control study design, we observed significant associations of atopy and asthma related phenotypes with several IL4Ra polymorphisms genotyped within the gene. The most significant association was observed with S478P, which was associated with high IgE levels (p = 0.0007). A significant gene-gene interaction was detected between the S478P variation in IL4Ra (significantly associated with high IgE levels) and the -1111 promoter variation in IL13 (significantly associated with bronchial hyperresponsiveness). Individuals with the risk genotype for both of these genes were at almost five times higher risk for the development of asthma compared to individuals with both non-risk genotypes (p = 0.0004). 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 the development of asthma.