Variants of STAT6 (signal transducer and activator of transcription 6) in atopic asthma

Editor—Atopy is characterised by raised IgE levels and it underlies the clinical disorder bronchial asthma.1-3 IL-4 and IL-13 play a key role in the development of asthma acting through the IL-4 receptor (IL-4R) and IL-13R, respectively.1-3 Since these two receptors share the IL-4Rα chain, this subunit is the crucial component required for IL-4 and IL-13 signalling.1-3 Recently, three coding variants in the human IL4R gene have been identified and these showed genetic and functional association with atopic asthma in different ethnic groups. The Ile50 variant was associated with atopic asthma in a Japanese population4 5and Arg551 or Pro478 were associated with IgE levels in American6 and German populations,7respectively, but perhaps through different mechanisms. Ile50 specifically and strongly upregulates cellular IgE synthesis through stat6 when tested by cDNA transfection into human and murine B cell lines.4 5 Functional assay of Arg551Gln IL-4Rα showed impaired binding of the negative regulatory molecule, protein tyrosine phosphatase, SHP-1, and increased expression of CD23 was found in peripheral blood mononuclear cells after challenge with human IL-4.6 However, this finding was not replicated by another group.8 In contrast, Pro478 is in tight linkage disequilibrium with Arg551 in a German population and may change the structure of the receptor, leading to altered phosphorylation patterns of signal molecules and hence lower IgE levels.7 These findings emphasise the genetic heterogeneity of atopy and question whether the molecular interaction between variants of IL-4Rα and its associated signal transduction molecules, such as stat6, may be important.1-3 The Stats are a family of transcription factors evolutionarily conserved from Drosophila to humans.9 To date seven different STAT genes have been identified in humans.9 Stat6 activation correlates with functional …