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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study made use of whole-genome data generated on MEC1 as part of the Singapore National Precision Medicine program funded by the Industry Alignment Fund (Pre-Positioning) (IAF-PP: H17/01/a0/007) S.C.R was supported by core funding from the: British Heart Foundation (RG/18/13/33946), the Munz Chair of Cardiovascular Prediction and Prevention and the NIHR Cambridge Biomedical Research Centre (NIHR203312) [*], Cambridge BHF Centre of Research Excellence (RE/18/1/34212) and BHF Chair Award (CH/12/2/29428) and by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome. *The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional Review Board of the National University of Singapore gave ethnical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Summary statistics for all measured proteins are provided in the Supplementary Tables. Data from the Singapore Multi-Ethnic Cohort Phase 1 study can be requested by researchers for scientific purposes through an application process at the listed website (https://blog.nus.edu.sg/sphs/data-and-samples-request/). Data will be shared through an institutional data sharing agreement.