TYK2 Promoter Variant and Diabetes Mellitus in the Japanese

Seiho Nagafuchi; Yumi Kamada-Hibio; Kanako Hirakawa; Nobutaka Tsutsu; Masae Minami; Akira Okada; Katsuya Kai; Miho Teshima; Arisa Moroishi; Yoshikazu Murakami; Yoshikazu Umeno; Yasushi Yokogawa; Kazuhiko Kogawa; Kenichi Izumi; Keizo Anzai; Ryuichi Iwakiri; Kazuyuki Hamaguchi; Nobuhiro Sasaki; Sakae Nohara; Eiko Yoshida; Mine Harada; Koichi Akashi; Toshihiko Yanase; Junko Ono; Toshimitsu Okeda; Ryoji Fujimoto; Kenji Ihara; Toshiro Hara; Yohei Kikuchi; Masanori Iwase; Takanari Kitazono; Fumiko Kojima; Suminori Kono; Hironori Kurisaki; Shiori Kondo; Hitoshi Katsuta

doi:10.1016/j.ebiom.2015.05.004

TYK2 Promoter Variant and Diabetes Mellitus in the Japanese

EBioMedicine. 2015 May 9;2(7):744-9. doi: 10.1016/j.ebiom.2015.05.004. eCollection 2015 Jul.

Authors

Seiho Nagafuchi¹, Yumi Kamada-Hibio², Kanako Hirakawa², Nobutaka Tsutsu³, Masae Minami⁴, Akira Okada⁵, Katsuya Kai², Miho Teshima², Arisa Moroishi², Yoshikazu Murakami⁶, Yoshikazu Umeno⁷, Yasushi Yokogawa⁸, Kazuhiko Kogawa⁸, Kenichi Izumi⁹, Keizo Anzai⁹, Ryuichi Iwakiri¹⁰, Kazuyuki Hamaguchi¹¹, Nobuhiro Sasaki³, Sakae Nohara³, Eiko Yoshida¹², Mine Harada¹², Koichi Akashi¹², Toshihiko Yanase¹³, Junko Ono¹³, Toshimitsu Okeda¹⁴, Ryoji Fujimoto¹⁴, Kenji Ihara¹⁵, Toshiro Hara¹⁵, Yohei Kikuchi¹⁶, Masanori Iwase¹⁶, Takanari Kitazono¹⁶, Fumiko Kojima², Suminori Kono¹⁷, Hironori Kurisaki², Shiori Kondo¹⁸, Hitoshi Katsuta¹

Affiliations

¹ 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.
² Department of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
³ Department of Diabetes and Metabolism, Fukuoka Red Cross Hospital, Fukuoka 815-8555, Japan.
⁴ Minami Masae Naika Clinic, Fukuoka 815-0071, Japan.
⁵ Okada Naika Clinic, Fukuoka 812-0053, Japan.
⁶ Yamaguchi Red Cross Hospital, Yamaguchi 753-8519, Japan.
⁷ Department of Diabetes, Oita Red Cross Hospital, Oita 870-0033, Japan.
⁸ Department of Internal Medicine, Hamanomachi Hospital, Fukuoka 810-8539, Japan.
⁹ Departmtent of Hepatology, Diabetes and Endocrinology, Saga University, Saga 849-8501, Japan.
¹⁰ Department of Internal Medicine & Gastrointestinal Endoscopy, School of Medicine, Saga University, Saga 849-8501, Japan.
¹¹ Department of Medicine, School of Medicine, Oita University, 849-8501, Oita 879-5593, Japan.
¹² Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
¹³ Department of Clinical Laboratory Medicine, School of Medicine, Fukuoka University, Fukuoka 814-0180, Japan ; Department of Diabetology and Metabolism, School of Medicine, Fukuoka University, Fukuoka 814-0180, Japan.
¹⁴ Department of Internal Medicine, Shinkokura Hospital, Kitakyushu 803-8505, Japan.
¹⁵ Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
¹⁶ Department of Medicine and Clinical Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
¹⁷ National Institute of Health and Nutrition, Tokyo 162-8636, Japan.
¹⁸ Matsuyama Red Cross Hospital, Matsuyama 790-8524, Japan.

Abstract

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.

Keywords: Diabetes mellitus; Polymorphism; Promoter variant; Tyrosine kinase 2 (TYK2); Virus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Age of Onset
Aged
Aged, 80 and over
Asian People / genetics*
Base Sequence
Case-Control Studies
Child
Diabetes Mellitus, Type 1 / enzymology*
Diabetes Mellitus, Type 1 / genetics*
Diabetes Mellitus, Type 2 / enzymology*
Diabetes Mellitus, Type 2 / genetics*
Female
Genetic Predisposition to Disease
Humans
Male
Middle Aged
Molecular Sequence Data
Polymorphism, Single Nucleotide / genetics*
Promoter Regions, Genetic / genetics*
TYK2 Kinase / genetics*
Young Adult

Substances

TYK2 Kinase