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
- P S Gao1,
- N M Heller1,
- W Walker2,
- C H Chen3,
- M Moller2,
- B Plunkett1,
- M H Roberts2,
- R P Schleimer1,
- J M Hopkin2,
- S K Huang1
- 1Johns Hopkins University School of Medicine, Johns Hopkins Asthma and Allergy Center, Baltimore, MD, USA
- 2Swansea Clinical School, University of Wales Swansea, Swansea, UK
- 3Taipei Medical University, Taipei, Taiwan, Republic of China
- Correspondence to: Dr P S Gao Johns Hopkins Asthma and Allergy Center, Room 1A62, 5501 Hopkins Bayview Circle, Baltimore, 21224, USA; pgao1jhmi.edu
- Received 16 December 2003
- Accepted 27 December 2003
Upregulation of the IL-4/IL-13 mediated Th2 response is a characteristic of allergic diseases such as asthma, a common and often debilitating disease.1 STAT6 is a critical signalling molecule in the Th2 signalling pathway, and mice lacking STAT6 are protected from allergic pulmonary manifestations.2 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.3 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-13.4 As a consequence, STAT6 has been considered a strong candidate for predisposition to atopic asthma. Indeed, the human STAT6 gene is mapped to chromosome 12q13.3−q14.1, a region linked to total serum IgE concentration and atopy in several populations.5 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 3′ untranslated region of the human STAT6 gene.6–9 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 enhanced10 or decreased transcriptional activity11,12 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-, H- and cruciform DNA.13 The Z-DNA sequences in human genes tend to be located near transcription sites, which makes it possible that they play …
