Plasma Proteins Associated With Incident Acute Myocardial Infarction in Asians With Type 2 Diabetes.
BACKGROUND Individuals with type 2 diabetes (T2D) have increased risk of acute myocardial infarction (AMI). Cardiovascular risk within T2D is heterogeneous and not fully explained by conventional risk factors, highlighting the need for improved biological risk stratification. OBJECTIVES The authors aimed to identify circulating proteins associated with incident AMI in T2D, evaluate their incremental predictive value, and explore potential causal relationships. METHODS In 1,830 adults with T2D from the prospective SMART2D cohort, 1,457 plasma proteins were quantified at baseline using Olink proximity extension assays. Participants were followed for incident AMI through linkage with the Singapore Myocardial Infarction Registry over a median of 10.2 years (IQR: 9.1-10.7). Multivariable Cox regression assessed protein-AMI association. Incremental predictive performance was evaluated using Harrell's C-statistic, likelihood ratio tests (LRTs), net reclassification index (NRI), and integrated discrimination index (IDI). Two-sample Mendelian randomization, using cis-protein qualitative-trait loci from SMART2D and outcome data from Biobank Japan (14,992 cases; 146,214 controls), examined causal associations. RESULTS During follow-up, 223 participants (12.2%) developed AMI. Seventeen proteins were independently associated with AMI after Bonferroni correction (P < 3.43 × 10-5), with the strongest associations observed for NEFL (HR: 1.70, 95% CI: 1.43-2.01), EDA2R (HR: 2.25, 95% CI: 1.69-2.97), and CHRDL1 (HR: 2.69, 95% CI: 1.83-3.94). An 8-protein panel improved risk classification beyond clinical variables (LRT P = 0.002; IDI: 0.049, 95% CI: 0.022-0.128, P = 0.002; and NRI: 0.318, 95% CI: 0.112-0.411, P = 0.008). Genetically predicted plasma FGF5 levels were associated with myocardial infarction risk. CONCLUSIONS Plasma proteomics improves AMI risk stratification in T2D, and FGF5 may play a role in cardiovascular risk in Asian populations.