Circulating proteomic profiles are associated with the onset of type 2 diabetes in a multi-ethnic Asian population -- a longitudinal study

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. To understand the protein function in incident T2D, 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). Our analysis revealed 522 proteins that were associated with incident T2D after adjusting for age, sex, and ethnicity. 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. Article HighlightsO_LIWe measured 4,775 proteins in 1,659 Asian participants and reported 522 proteins (316 novel) associated with incident type 2 diabetes (T2D). C_LIO_LIOf 479 proteins previously reported to be associated with T2D, 384 (80.17%) showed same direction of effects in our study. C_LIO_LIMany of the incident T2D-associated proteins were also associated with insulin resistance markers including waist circumference and triglycerides. C_LIO_LIMendelian randomization analysis identified three proteins, GSTA1, INHBC, and FGL1, to have plausible casual associations with T2D development. Colocalization analysis and previous studies further supported GSTA1 and INHBC as candidate causal proteins. C_LI