Identification of a novel type 1 diabetes susceptibility gene, T-bet.
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.
Sasaki
Yuka
Y
Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Japan. yuka@pediatr.med.kyushu-u.ac.jp
Ihara
Kenji
K
Matsuura
Nobuo
N
Kohno
Hitoshi
H
Nagafuchi
Seiho
S
Kuromaru
Ryuichi
R
Kusuhara
Koichi
K
Takeya
Ryu
R
Hoey
Timothy
T
Sumimoto
Hideki
H
Hara
Toshiro
T
D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000096:biosynthesis*; D007438:Introns; D008297:Male; D018895:Microsatellite Repeats; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D020825:T-Box Domain Proteins; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D000098815:T-bet Transcription Factor
D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D007371:Interferon-gamma