Identification of a novel type 1 diabetes susceptibility gene, T-bet
Identification of a novel type 1 diabetes susceptibility gene, T-bet
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DOI：
10.1007/s00439-004-1146-2
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发表时间：
2004-08-01
期刊：
影响因子：
5.3
通讯作者：
Hara, T
中科院分区：
文献类型：
--
作者：
Sasaki, Y;Ihara, K;Hara, T
干扰素-γ编码基因IFNG被认为是1型糖尿病的候选易感基因之一。此外，包括干扰素-γ在内的细胞因子在1型糖尿病的发病机制中发挥着重要作用。因此，我们重点研究了Th1特异性T-box转录因子基因(T-bet)，它参与了Th1标志性细胞因子--干扰素-γ的诱导。我们首先检测了T-bet基因的多态性，发现了位于内含子1和3‘-侧翼区的两个微卫星重复序列多态，以及两个单核苷酸多态，包括编码区内的His33Gln替换。相关研究发现，T-bet基因3‘侧翼区的Gln阳性表型和(CA)(14)等位基因与日本人群中的1型糖尿病相关。此外，通过双荧光素酶报告基因分析，Gln33T-bet显示了显著更高的IFNG基因转录活性。我们的研究首次提出了1型糖尿病与T-bet基因多态有关的证据，T-bet转录活性的变化可能通过影响Th1细胞中干扰素-γ的产生而在1型糖尿病的发生发展中发挥作用。
The gene encoding interferon (IFN)-gamma, IFNG, is known as one of the candidate susceptibility genes for type 1 diabetes. In addition, cytokines, including IFN-gamma, play important roles in the pathogenesis of type 1 diabetes. Therefore, we focused on the Th1-specific T-box transcription factor gene (T-bet), which contributes to the induction of the hallmark Th1 cytokine, IFN-gamma. We first screened for polymorphisms in the T-bet gene and detected two microsatellite repeat polymorphisms located in intron 1 and the 3'- flanking region, and two single nucleotide polymorphisms, including a His33Gln substitution within the coding region. By association studies, the Gln-positive phenotype and (CA)(14) allele in 3'-flanking region of T-bet were found to be associated with type 1 diabetes in the Japanese population. Furthermore, Gln33 T-bet showed a significantly higher transcriptional activity of the IFNG gene via a dual luciferase reporter assay. Our study suggests the first evidence of an association between type 1 diabetes and polymorphisms in the T-bet gene, and that variation in T-bet transcriptional activity may play a role in the development of type 1 diabetes, possibly through the effect on IFN-gamma production in Th1 cells.