Variants of IL-4RA and atopy

Atopy is characterized by heightened IgE levels and the TH2 cytokine IL-4 plays a crucial role, through the IL-4 receptor(IL-4R), in the IgE-dependent atopic disorders, asthma, eczema, and rhinitis. Two variants of IL-4Rα has been identified in association with different phenotypes of atopic disorders through different mechanisms(N Engl J Med 1997;337:1720, Nat Genet 1998;19:119). To clarify the aetiological interaction among variants of IL-4Rα, we conducted a large scale association study in British(n=300) and Japanese(n=400) populations. We identified another variant, Pro478Ser in a cytoplasmic portion of IL-4Rα by SSCP analysis. In a British population, the Ile50 was more frequent than that in a Japanese population; however, none of the 3 variants(Ile50Val, Pro478Ser, Arg551Gln) associated with atopy, though the Arg551 showed a marginal negative association (OR=0.265, p=0.0558) with atopy; this effect is recessive, not dominant as reported by Chatila's group in relation to severe eczema and hyper-IgE syndrome(N Engl J Med 1997;337:1720). These findings are concordant with those in a German population(more significant). In a Japanese population, atopy was strongly associated with the Ile50 variant of IL-4Rα (OR=6.77, p<0.0001), but not with other two variants. These results clealy illustrate that (1) the genotype frequencies of the 3 variants are different among different ethnic groups, (2) in a British population, none of the variants showed a strong association with atopy, (3) the Arg551 and Pro478 might be negatively associated with atopy in a Caucasians, while the Ile50 associates with atopy in a Japanese population. Functional analysis has demonstrated that the Ile50 upregulates cellular IgE synthesis, but that the Arg551 does not. We hypothesize that variants in upstream or downsteam molecules of IL-4Rα may modify the action of IL-4Rα variants among different ethnic groups on the complex trait of atopy.