日本人群中酪氨酸激酶2（TYK2）启动子变异与糖尿病
TYK2 Promoter Variant and Diabetes Mellitus in the Japanese.
作者信息
Nagafuchi Seiho, Kamada-Hibio Yumi, Hirakawa Kanako, Tsutsu Nobutaka, Minami Masae, Okada Akira, Kai Katsuya, Teshima Miho, Moroishi Arisa, Murakami Yoshikazu, Umeno Yoshikazu, Yokogawa Yasushi, Kogawa Kazuhiko, Izumi Kenichi, Anzai Keizo, Iwakiri Ryuichi, Hamaguchi Kazuyuki, Sasaki Nobuhiro, Nohara Sakae, Yoshida Eiko, Harada Mine, Akashi Koichi, Yanase Toshihiko, Ono Junko, Okeda Toshimitsu, Fujimoto Ryoji, Ihara Kenji, Hara Toshiro, Kikuchi Yohei, Iwase Masanori, Kitazono Takanari, Kojima Fumiko, Kono Suminori, Kurisaki Hironori, Kondo Shiori, Katsuta Hitoshi
机构信息
Department of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan ; Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan ; Department of Internal Medicine, Sawara Hospital, Sawara, Fukuoka 819-0002, Japan.
Department of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
出版信息
EBioMedicine. 2015 May 9;2(7):744-9. doi: 10.1016/j.ebiom.2015.05.004. eCollection 2015 Jul.
BACKGROUND
Recently, natural mutation of Tyrosine kinase 2 (Tyk2) gene has been shown to determine susceptibility to murine virus-induced diabetes. In addition, a previous human genome-wide study suggested the type 1 diabetes (T1D) susceptibility region to be 19p13, where the human TYK2 gene is located (19p13.2).
METHODS
Polymorphisms of TYK2 gene at the promoter region and exons were studied among 331 healthy controls, and 302 patients with T1D and 314 with type 2 diabetes (T2D) in the Japanese.
FINDINGS
A TYK2 promoter haplotype with multiple genetic polymorphisms, which are in complete linkage disequilibrium, named TYK2 promoter variant, presenting decreased promoter activity, is associated with an increased risk of not only T1D (odds ratio (OR), 2.4; 95% confidence interval (CI), 1.2 to 4.6; P = 0.01), but also T2D (OR, 2.1; 95% CI, 1.1 to 4.1; P = 0.03). The risk is high in patients with T1D associated with flu-like syndrome at diabetes onset and also those without anti-glutamic acid decarboxylase autoantibody.
INTERPRETATION
The TYK2 promoter variant is associated with an overall risk for diabetes, serving a good candidate as a virus-induced diabetes susceptibility gene in humans.
FUNDING
Ministry of Education, Culture, Sports, Science and Technology and of Health, Labor and Welfare of Japan.
背景
最近研究表明，酪氨酸激酶2（Tyk2）基因的自然突变决定了小鼠对病毒诱导糖尿病的易感性。此外，之前一项人类全基因组研究表明，1型糖尿病（T1D）的易感区域位于19号染色体短臂1区3带（19p13），人类TYK2基因也位于该位置（19p13.2）。
方法
在331名健康对照者、302名T1D患者和314名2型糖尿病（T2D）患者中，研究了日本人TYK2基因启动子区域和外显子的多态性。
研究结果
一种具有多个完全连锁不平衡遗传多态性的TYK2启动子单倍型，称为TYK2启动子变异体，其启动子活性降低，不仅与T1D风险增加相关（优势比（OR）为2.4；95%置信区间（CI）为1.2至4.6；P = 0.01），还与T2D风险增加相关（OR为2.1；95% CI为1.1至4.1；P = 0.03）。在糖尿病发病时伴有流感样综合征的T1D患者以及无抗谷氨酸脱羧酶自身抗体的患者中，这种风险更高。
解读
TYK2启动子变异体与糖尿病的总体风险相关，是人类病毒诱导糖尿病易感基因的良好候选者。
资金来源
日本文部科学省以及厚生劳动省。
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