Association of circulating metabolites and polygenic risk score with incident type 2 diabetes: a prospective community-based cohort study.

IF 10.6 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Cardiovascular Diabetology Pub Date : 2025-08-14 DOI:10.1186/s12933-025-02849-8

Masato Takase, Naoki Nakaya, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ippei Chiba, Sayuri Tokioka, Kotaro Nochioka, Tomohiro Nakamura, Naho Tsuchiya, Takumi Hirata, Seizo Koshiba, Kazuki Kumada, Ikuko Motoike, Eiji Hishinuma, Akira Narita, Taku Obara, Mami Ishikuro, Hisashi Ohseto, Ippei Takahashi, Tomoko Kobayashi, Eiichi N Kodama, Yohei Hamanaka, Masatsugu Orui, Soichi Ogishima, Satoshi Nagaie, Nobuo Fuse, Junichi Sugawara, Shinichi Kuriyama, Koichi Matsuda, Yoko Izumi, Kinuko Ohneda, Kengo Kinoshita, Atsushi Hozawa, Masayuki Yamamoto

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引用次数: 0

Abstract

Background: No previous studies have explored metabolites associated with both genetic predispositions to type 2 diabetes (T2DM) and T2DM onset. Therefore, we aimed to explore metabolic profiles using genetic risk to identify pathways for tailored T2DM prevention strategies.

Methods: This prospective community-based cohort study in Japan included a total of 12,461 participants aged ≥ 20 years. Genetic predictors were genome-wide and pathway-based polygenic risk scores (PRSs). We quantified 43 metabolites using nuclear magnetic resonance spectroscopy. T2DM was defined as a non-fasting glucose level of ≥ 200 mg/dL, glycated hemoglobin level ≥ 6.5%, or self-reported T2DM treatment. A modified Poisson regression model was used to examine the associations of PRSs and metabolites with T2DM incidence. Linear associations were tested using the restricted cubic spline, and mediation analysis was conducted to assess the mediating effect of metabolites on the association between PRSs and T2DM incidence.

Results: During the 4.3-year median follow-up period, 354 T2DM cases were identified. A higher PRS was associated with incident T2DM (relative risk [RR] 2.09, 95% confidence interval [CI], 1.68-2.60, P < 0.001, 1-standard deviation [SD] increment). The nitrogen compound transport pathway PRS was associated with incident T2DM (RR 1.32, 95% CI 1.03-1.70, P < 0.001, 1-SD increment). Fourteen metabolites like glucose, 2-ketoisocaproic acid, glutamic acid, leucine, 2-aminobutyric acid, 2-hydroxybutyric acid, valine, 3-methyl-2-oxobutyric acid, alanine, 3-hydroxybutyric acid, 3-methyl-2-oxiovaleric acid, formic acid, arginine, and tyrosine were positively associated with the risk of T2DM. Only glycine was inversely associated with the risk of T2DM. Among 43 metabolites, 14 metabolites were positively associated with PRS (P for linear trend < 0.05). 3-hydroxyisobutyric-acid, 2-Aminobutyric acid, 2-ketoisocaproic acid, 2-hydroxybutyric acid, leucine, glycine, and glucose mediated the association between PRS and incident T2DM.

Conclusions: Several metabolites were found to mediate the association between PRS and incident T2DM. These findings may contribute to a better understanding of the metabolic pathways involved in genetic susceptibility to T2DM.

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循环代谢物和多基因风险评分与2型糖尿病的关联：一项前瞻性社区队列研究

背景：以前没有研究探索与2型糖尿病（T2DM）遗传易感性和T2DM发病相关的代谢物。因此，我们的目的是利用遗传风险来探索代谢谱，以确定定制T2DM预防策略的途径。方法：这项前瞻性社区队列研究在日本纳入了12461名年龄≥20岁的参与者。遗传预测因子是全基因组和基于通路的多基因风险评分（PRSs）。我们用核磁共振光谱对43种代谢物进行了定量分析。T2DM定义为非空腹血糖水平≥200mg /dL，糖化血红蛋白水平≥6.5%，或自我报告T2DM治疗。采用改进的泊松回归模型来检验PRSs和代谢物与T2DM发病率的关系。使用受限三次样条检验线性关联，并进行中介分析以评估代谢物在PRSs与T2DM发病率之间的中介作用。结果：在4.3年的中位随访期间，共发现354例T2DM病例。较高的PRS与T2DM发病相关（相对危险度[RR] 2.09, 95%可信区间[CI]， 1.68-2.60， P）。结论：发现几种代谢物介导了PRS与T2DM发病之间的关联。这些发现可能有助于更好地理解与2型糖尿病遗传易感性相关的代谢途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cardiovascular Diabetology 医学-内分泌学与代谢

CiteScore

12.30

自引率

15.10%

发文量

240

审稿时长

1 months

期刊介绍： Cardiovascular Diabetology is a journal that welcomes manuscripts exploring various aspects of the relationship between diabetes, cardiovascular health, and the metabolic syndrome. We invite submissions related to clinical studies, genetic investigations, experimental research, pharmacological studies, epidemiological analyses, and molecular biology research in this field.