Abstract
BACKGROUND: Type 1 diabetes increases the risk of coronary artery disease (CAD). High-throughput metabolomics may be utilized to identify metabolites associated with disease, thus, providing insight into disease pathophysiology, and serving as predictive markers in clinical practice. Urine is less tightly regulated than blood, and therefore, may enable earlier discovery of disease-associated markers. We studied urine metabolomics in relation to incident CAD in individuals with type 1 diabetes. METHODS: We prospectively studied CAD in 2501 adults with type 1 diabetes from the Finnish Diabetic Nephropathy Study. 209 participants experienced incident CAD within the 10-year follow-up. We analyzed the baseline urine samples with a high-throughput targeted urine metabolomics platform, which yielded 54 metabolites. With the data, we performed metabolome-wide survival analyses, correlation network analyses, and metabolomic state profiling for prediction of incident CAD. RESULTS: Urinary 3-hydroxyisobutyrate was associated with decreased 10-year incident CAD, which according to the network analysis, likely reflects younger age and improved kidney function. Urinary xanthosine was associated with 10-year incident CAD. In the network analysis, xanthosine correlated with baseline urinary allantoin, which is a marker of oxidative stress. In addition, urinary trans-aconitate and 4-deoxythreonate were associated with decreased 5-year incident CAD. Metabolomic state profiling supported the usage of CAD-associated urinary metabolites to improve prediction accuracy, especially during shorter follow-up. Furthermore, urinary trans-aconitate and 4-deoxythreonate were associated with decreased 5-year incident CAD. The network analysis further suggested glomerular filtration rate to influence the urinary metabolome differently between individuals with and without future CAD. CONCLUSIONS: We have performed the first high-throughput urinary metabolomics analysis on CAD in individuals with type 1 diabetes and found xanthosine, 3-hydroxyisobutyrate, trans-aconitate, and 4-deoxythreonate to be associated with incident CAD. In addition, metabolomic state profiling improved prediction of incident CAD.