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Identification of a novel type 1 diabetes susceptibility gene, T-bet

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Abstract

The gene encoding interferon (IFN)-γ, IFNG, is known as one of the candidate susceptibility genes for type 1 diabetes. In addition, cytokines, including IFN-γ, 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-γ. 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-γ production in Th1 cells.

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Acknowledgments

We extend special thanks to Dr. K. Miyako, Department of Endocrinology and Metabolism, Fukuoka Children’s Hospital for the patient samples. This work was supported by the grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and from Japanese Study Group for Pediatric and Adolescent Diabetes.

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Authors and Affiliations

  1. Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Yuka Sasaki, Kenji Ihara, Ryuichi Kuromaru, Koichi Kusuhara & Toshiro Hara

  2. Department of Internal Medicine, Kyushu University, Fukuoka, Japan

    Seiho Nagafuchi

  3. Graduate School of Medical Sciences, and Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

    Yuka Sasaki, Ryu Takeya & Hideki Sumimoto

  4. Department of Pediatrics, Kitasato University School of Medicine, Kanagawa, Japan

    Nobuo Matsuura

  5. Department of Endocrinology and Metabolism, Fukuoka Children’s Hospital, Fukuoka, Japan

    Hitoshi Kohno

  6. Tularik Inc., California, USA

    Timothy Hoey

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  1. Yuka Sasaki
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Correspondence to Yuka Sasaki.

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Sasaki, Y., Ihara, K., Matsuura, N. et al. Identification of a novel type 1 diabetes susceptibility gene, T-bet. Hum Genet 115, 177–184 (2004). https://doi.org/10.1007/s00439-004-1146-2

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