V75R576 IL-4 receptor α is associated with allergic asthma and enhanced IL-4 receptor function

Asthma is a complex polygenic disease. Many, studies have implicated the importance of IL-4Ralpha in the development of allergic inflammation and its gene has been implicated in the genetics of asthma and atopy. In this study, we examined the functional consequences of two of the human IL-4Ralpha allelic variants that have been found to associate with asthma and atopy. We examined the effects of each variant alone and in combination on IL-4-dependent gene induction. We found that neither the Q576R nor the 175V variants affected IL-4-dependent CD23 expression. However, the combination of V75R576 resulted in expression of an IL-4Ralpha with enhanced sensitivity to IL-4. We next examined the genetics of five of the known IL-4Ralpha allelic variants in asthmatic and nonatopic populations. Strikingly, the association of V75/R576 with atopic asthma A as greater than either allele alone and the association of R576 with atopic asthma was dependent on the coexistence of V75. A haplotype analysis revealed a single IL-4Ralpha haplotype that was associated with allergic asthma, VACRS, further confirming the importance of the V75 and R576 combination in the genetics of asthma. This is the first report demonstrating that a functional alteration in IL-4Ralpha requires the coexistence of two naturally occurring single nucleotide polymorphisms (snps) in combination, neither snp alone is sufficient. These data illustrate the importance of studying sups in combination, because the functional significance of a given snp may only be evident in a specific setting of additional snps in the same or different genes.