TY - JOUR
T1 - Identification of a novel type 1 diabetes susceptibility gene, T-bet
AU - Sasaki, Yuka
AU - Ihara, Kenji
AU - Matsuura, Nabuo
AU - Kohno, Hitoshi
AU - Nagafuchi, Seiho
AU - Kuromaru, Ryuichi
AU - Kusuhara, Koichi
AU - Takeya, Ryu
AU - Hoey, Timothy
AU - Sumimoto, Hideki
AU - Hara, Toshiro
N1 - Funding Information:
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.
PY - 2004/8
Y1 - 2004/8
N2 - 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.
AB - 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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U2 - 10.1007/s00439-004-1146-2
DO - 10.1007/s00439-004-1146-2
M3 - Article
C2 - 15241679
AN - SCOPUS:4344626455
SN - 0340-6717
VL - 115
SP - 177
EP - 184
JO - Human Genetics
JF - Human Genetics
IS - 3
ER -
