Prior studies of biomarkers for coronary artery disease (CAD) in the high-risk type 1 diabetes (T1D) population focused on candidate proteins but such analyses may miss the complex systemic process underlying atherosclerosis. High-throughput proteomics facilitate a systems approach to identify pathways associated with risk. Thus, we hypothesized that protein networks are associated with 30-year incident CAD (CAD death, myocardial infarction, coronary revascularization/blockage≥50%) in the Pittsburgh Epidemiology of Diabetes Complications study of childhood-onset (<17 yrs) T1D (n=421 with available stored serum specimens prior to first CAD, mean age 30 yrs, T1D duration range 7-42 yrs at baseline). We measured 184 circulating proteins (Olink Proteomics CVD II and CVD III panels) in each participant’s earliest serum sample. Protein modules were identified using weighted co-expression network analysis. Pathway enrichment analysis was performed using all proteins on the panels as background. Prospective associations between modules (per eigenvalue standard deviation) and CAD incidence were estimated in Cox models adjusted for covariates concurrent with the serum sample, including age, sex, sample visit, smoking, blood pressure and lipid lowering medications, eGFR, and HbA1c. Associations between individual proteins (per 2-fold increment) and CAD incidence were also estimated. We identified 3 modules: Module 1 (Brown, 33 proteins) was primarily enriched for “lipid catabolic process”, Module 2 (Turquoise, 56 proteins) for "cytokine-cytokine receptor interaction”, and Module 3 (Blue, 33 proteins) for "platelet alpha granule”. Incident CAD occurred in 151 participants (36.2%). Module 1 was associated with reduced CAD (HR=0.82, 95% CI:0.70-0.96, p=0.014), Module 2 with increased CAD (HR=1.35, 95% CI:1.06-1.72, p=0.017), and Module 3 was not associated. Alpha-1-Microglobulin/Bikunin Precursor (AMBP, HR=2.68, 95% CI:1.64-4.29, p<0.0001) in Module 2 was the top individual protein associated with CAD. While not members of any module, LDL receptor protein (HR= 1.49, 95% CI: 1.22-1.82, p=0.0001) and fatty acid binding protein 4 (FABP4, HR=1.39, 95% CI: 1.17-1.66, p=0.0002) were also associated with CAD. In conclusion our results suggest opposing pathways may influence CAD in T1D, including a protective role of lipid catabolism and detrimental role of cytokine signaling, which warrant further study to determine if they improve risk prediction beyond clinical risk factors.
Zhou et al. (Tue,) studied this question.