Analysis of the Ser786Pro interleukin-4 receptor alpha allelic variant in allergic and nonallergic asthma and its functional consequences

Asthma and other atopic disorders affect a large percentage of the populati on. While many factors contribute to the phenotype of asthma, there is a st rong genetic predisposition. IL-4 is a central mediator of allergic inflamm ation. Along with IL-13, it is the major cytokine responsible for the induc tion of IgE synthesis. Furthermore, IL-4 acts on Th0 cells and promotes the ir differentiation into Th2 cells resulting in the production of more IL-4 and IL-13, thereby propagating the allergic cascade. Both IL-4 and IL-13 ut ilize IL-4R alpha as a component of their cognate receptor complexes. Eight polymorphisms of the IL-4R alpha gene resulting in amino acid changes in t he coding sequence have been described, and several have been associated wi th asthma. The central objective of this study was to elucidate the role of the Ser786Pro polymorphism in asthma and its impact on IL-4R function. One -hundred ninety-six individuals with asthma and 53 controls were genotyped for Pro786. Pro786 occurred infrequently in the general population with an allele frequency of 1.8% and, thus, is unlikely to play a major role in ato py or asthma. The Pro786 allele frequency was 1.5% in the asthma group and 2.8% in the control group. The asthma group was subdivided into allergic an d nonallergic asthma, and the Pro786 allele frequencies were 1.7 and 1.0%, respectively. The data suggested linkage disequilibrium between Ser786Pro a nd the Gin576Arg allele, which is associated with atopy. In order to study the impact of the polymorphism on receptor signaling function, we transfect ed a mouse B lymphoma cell line with the wild-type and Pro786 variants of h uman IL-4Ra. The Ser786Pro polymorphism in isolation did not affect IL-4R f unction. (C) 2001 Academic Press.