A novel polymorphic GATA site in the human IL-12Rβ2 promoter region affects transcriptional activity

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Abstract

Interleukin-12 (IL-12) is a potent inducer of interferon-γ production by T cells and is a major factor for the development of T-helper 1 (Th1) cells. It exerts its biological effects through binding to the IL-12 receptor (IL-12R), a heterodimer composed of a 1 and a β2 subunits. The signaling β2 chain is expressed on Th1 cells and to a lesser extent on Th0 cells, but not on Th2 cells, rendering these latter cells unresponsive to IL-12. Polymorphisms in the coding region of the IL-12Rβ2 gene were shown to be associated with atopic disease. Here, we analyzed the 5′-regulatory region of the human IL-12Rβ2 gene by denaturing high-performance liquid chromatography (Transgenomic WAVE system, San Jose, CA). We found five novel single-nucleotide polymorphisms (SNPs) in the proximal 1.2 kb IL-12Rβ2 promoter region, i.e. −237C/T, −465A/G, −1023A/G, −1033T/C, and −1035A/G. SNP −465A/G is of particular interest as it determines the integrity of a GATA consensus site. By functional comparison of both −465 alleles in transient transfection assays, we show that promoter activity is increased in case of the −465G allele, disrupting the intact GATA site. Comparison of the prevalence of −465A/G SNP alleles in small cohorts of allergic asthmatic and healthy control individuals provided no evidence for an altered distribution in the asthmatic population. In conclusion, we have identified a novel polymorphic GATA site that may affect transciptional activity of the human IL-12Rβ2 gene under GATA3-mediated, Th2-polarizing conditions.

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