Abstract
CONTEXT: 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. OBJECTIVE: The aim of this study was to investigate the relationship between plasma proteins and the incidence of T2D in Asian individuals. METHODS: We examined the association of 4775 plasma proteins with incident T2D in a Singapore multi-ethnic cohort of 1659 Asian individuals (539 cases and 1120 controls) using logistic regression. We used 2-sample mendelian randomization and colocalization analysis to evaluate the causal relationship between proteins and T2D. RESULTS: Our analysis revealed 522 proteins that were associated with incident T2D after adjusting for age, sex, and ethnicity, and 17 proteins that remained statistically 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 6-year 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 3 plasma proteins, GSTA1, INHBC, and FGL1, play causal roles in the development of T2D, with colocalization evidence supporting GSTA1 and INHBC. CONCLUSION: Our findings reveal plasma protein profiles linked to the onset of T2D in Asian populations, offering insights into the biological mechanisms of T2D development.