Variation in dinucleotide (GT) repeat sequence in the first exon of the STAT6 gene is associated with atopic asthma and differentially regulates the promoter activity in vitro.
U pregulation of the IL-4/IL-13 mediated Th2 response is a characteristic of allergic diseases such as asthma, a common and often debilitating disease. STAT6 is a critical signalling molecule in the Th2 signalling pathway, and mice lacking STAT6 are protected from allergic pulmonary manifestations. The importance of STAT6 in asthma is also evident from studies showing that STAT6 gene expression is markedly upregulated in airway epithelial cells in asthma. STAT6 is important in the expression of VCAM-1 in endothelial cells and of chemokines, such as eotaxin, in epithelial cells following stimulation with IL-4 and IL-13. As a consequence, STAT6 has been considered a strong candidate for predisposition to atopic asthma. Indeed, the human STAT6 gene is mapped to chromosome 12q13.32q14.1, a region linked to total serum IgE concentration and atopy in several populations. A number of common polymorphisms have been identified, including a GT repeat in exon 1 and three common SNPs (G4219A, A4491G, and A4671G; GenBank AF067575) in the 39 untranslated region of the human STAT6 gene. Although all four of these polymorphisms have been shown to be associated with allergic phenotypes in various populations, their functional relevance remains unclear. Dinucleotide repeats are the most frequent of the simple repeats distributed throughout the human genome, and many of these exhibit length polymorphisms. Investigations into the effect of dinucleotide repeats on gene expression have shown enhanced or decreased transcriptional activity 12 in the context of different genes and cell types. These regulatory effects have been proposed to be due, in part, to the fact that dinucleotide repeats have potential to form alternative DNA structures, such as Z-, Hand cruciform DNA. The Z-DNA sequences in human genes tend to be located near transcription sites, which makes it possible that they play a role in the transcriptional control of genes. Because of their close proximity to the transcription start site, we first conducted a case2control association analysis of the GT repeat variants and atopic phenotypes in a white population, and then investigated their potential functional effects on the regulation of the activity of the STAT6 promoter. We report, for the first time, that the GT13 repeat variant in exon 1 of STAT6 is associated with asthma and total serum IgE level in a white study population, and that variation in the length of repeat variants differentially regulates the promoter activity in vitro.