Liang Yujian, Lim Charlie G Y, Ritchie Scott C, Bertin Nicolas, Chai Jin-Fang, Yao Jiali, Li Yun, Tai E Shyong, van Dam Rob M, Sim Xueling
Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.
Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
J Clin Endocrinol Metab. 2025 Jan 22. doi: 10.1210/clinem/dgaf045.
Type 2 diabetes (T2D) is a major global concern, with Asia at its epicenter in recent years. Proteins, products of gene transcription, serve as dynamic biomarkers for pinpointing perturbed pathways in disease development. Previous T2D proteomic association studies primarily focused on European populations.
The aim of this study was to investigate the relationship between plasma proteins and the incidence of T2D in Asian participants.
We examined the association of 4,775 plasma proteins with incident T2D in a Singapore multi-ethnic cohort of 1,659 Asian participants (539 cases and 1,120 controls) using logistic regression. We used two-sample Mendelian randomization and colocalization analysis to evaluate the causal relationship between proteins and T2D.
Our analysis revealed 522 proteins that were associated with incident T2D after adjusting for age, sex, and ethnicity, and 17 proteins that remained significantly associated after adjusting for other T2D risk factors such as fasting glucose, waist circumference, and triglycerides. Among the 522 proteins associated with incident T2D, the change in 205 plasma proteins, observed in parallel with the development of T2D at baseline and six-years follow-up, were further associated with incident T2D. The associated proteins showed enrichment in neuron generation, glycosaminoglycan binding, and insulin-like growth factor binding. Two-sample Mendelian randomization analysis suggested three plasma proteins, GSTA1, INHBC, and FGL1, play causal roles in the development of T2D, with colocalization evidence supporting GSTA1 and INHBC.
Our findings reveal plasma protein profiles linked to the onset of T2D in Asian populations, offering insights into the biological mechanisms of T2D development.
2型糖尿病（T2D）是全球主要关注的问题，近年来亚洲是其中心。蛋白质作为基因转录的产物，是用于确定疾病发展中受干扰途径的动态生物标志物。先前的T2D蛋白质组关联研究主要集中在欧洲人群。
本研究旨在调查亚洲参与者血浆蛋白与T2D发病率之间的关系。
我们在一个由1659名亚洲参与者（539例病例和1120名对照）组成的新加坡多民族队列中，使用逻辑回归分析了4775种血浆蛋白与新发T2D的关联。我们使用两样本孟德尔随机化和共定位分析来评估蛋白质与T2D之间的因果关系。
我们的分析显示，在调整年龄、性别和种族后，有522种蛋白质与新发T2D相关，在调整其他T2D风险因素（如空腹血糖、腰围和甘油三酯）后，有17种蛋白质仍显著相关。在与新发T2D相关的522种蛋白质中，在基线和六年随访中与T2D发展同时观察到的205种血浆蛋白的变化，进一步与新发T2D相关。相关蛋白质在神经元生成、糖胺聚糖结合和胰岛素样生长因子结合方面表现出富集。两样本孟德尔随机化分析表明，三种血浆蛋白GSTA1、INHBC和FGL1在T2D的发展中起因果作用，共定位证据支持GSTA1和INHBC。
我们的研究结果揭示了与亚洲人群T2D发病相关的血浆蛋白谱，为T2D发展的生物学机制提供了见解。
