Dataset Information

TYK2 Promoter Variant and Diabetes Mellitus in the Japanese.

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.

SUBMITTER: Nagafuchi S

PROVIDER: S-EPMC4534683 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

TYK2 Promoter Variant and Diabetes Mellitus in the Japanese.

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

EBioMedicine 20150509 7

<h4>Background</h4>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).<h4>Methods</h4>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) ...[more]

PMID: 26288847

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Project description:AimsSarcolipin (SLN) is a key regulator of sarcoplasmic reticulum calcium-ATPase (SERCA)2a, which handles intracellular calcium re-uptake. This study was aimed to investigate the involvement of SLN in post-myocardial infarction (MI) heart failure (HF) in diabetes.Methods and resultsDiabetes/MI rat models were established. Altered SLN expression in diabetic hearts was screened out by microarray. A myocardiotropic viral vector was used to deliver siRNA to silence SLN. DNA methylation was evaluated by bisulfite sequencing. Cardiac functions were evaluated by invasive haemodynamic examinations. The SERCA2a activity, cytoplasmic calcium concentration ([Ca2+ ]i ), calcium spark, and myocyte contraction were detected. Correlation between HF and diabetes was analysed in a cohort consisted of 101 ST-segment elevated myocardial infarction (STEMI) patients between 2017 and 2019 [53.54 ± 4.64 years old; 61.4% male gender; HbA1c% 6.15 ± 2.00; and left ventricular ejection fraction (LVEF%) 40.64 ± 3.20%]. SLN expression was evaluated in left ventricular tissue sample from six STEMI patients complicated with diabetes and six STEMI patients without diabetes. Expressions of DNA methyltransferase 1a and DNA methyltransferase 3 were reduced in diabetic hearts, leading to down-regulation of SLN promoter methylation, resulting in increased SLN expression in rats. Impaired heart systolic functions were found in experimental diabetic MI rats, which were attenuated by SLN silencing. SERCA2a activity reduction and [Ca2+ ]i elevation were attenuated by SLN silencing in diabetic animal hearts and high-glucose incubated primary myocytes. SLN silencing suppressed calcium sparks and improved contraction and sarcoplasmic reticulum calcium re-uptake in high-glucose incubated primary myocytes. Expression of SLN was up-regulated in LV sampled from STEMI patients complicated with diabetes compared with non-diabetic ones (P < 0.05). LVEF% was reduced in STEMI patients complicated with diabetes compared with non-diabetic ones (P < 0.01). HbA1c% and LVEF% was related (r = -0.218, P = 0.028). Increased HbA1c% was correlated with reduced LVEF% after adjustment for age, sex, body mass index, cigarette smoking, creatinine, UA, low density lipoprotein, K+ , Na+ , and troponin I (adjusted odds ration = 0.75, 95% confidence interval 0.62-0.90, P = 0.002).ConclusionsDiabetes increases the vulnerability of STEMI patients to post-MI HF by down-regulating SLN promoter methylation, which further regulates SERCA2a activity via increasing cardiac SLN expression.

Dataset Information

TYK2 Promoter Variant and Diabetes Mellitus in the Japanese.

Background

Methods

Findings

Interpretation

Funding

Publications

TYK2 Promoter Variant and Diabetes Mellitus in the Japanese.

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