Serum orotidine: a novel biomarker of increased CVD risk in type 2 diabetes discovered through metabolomics studies
Objective: To identify novel biomarkers of cardiovascular disease (CVD) risk in type 2 diabetes (T2D) via a hypothesis-free global metabolomics study, while taking into account renal function, an important confounder often overlooked by previous metabolomics studies of CVD.
Research Design and Methods: We conducted a global serum metabolomics analysis (Metabolon) in a Discovery Set from the Joslin Kidney Study having a nested case-control design comprising 409 individuals with T2D. Logistic regression was applied to evaluate the association between incident CVD events and each of the 671 metabolites detected by the Metabolon platform, before and after adjustment for renal function and other CVD risk factors. Significant metabolites were followed-up with absolute quantification assays in a Validation Set from the Joslin Heart Study including 599 individuals with T2D, with and without clinical evidence of significant coronary heart disease (CHD).
Results: In the Discovery Set, serum orotidine and 2-piperidinone were significantly associated with increased odds of incident CVD after adjustment for GFR (OR per SD increment=1.94, 95% CI 1.39-2.72, p=0.0001, and 1.62, 95% CI 1.26-2.08, p=0.0001, respectively). Orotidine was also associated with increased odds of CHD in the Validation Set (OR=1.39, 95% CI 1.11-1.75), while 2-piperidinone did not replicate. Furthermore, orotidine, being inversely associated with GFR, mediated 60% of the effects of declining renal function on CVD risk. Addition of orotidine to established clinical predictors improved (p<0.05) c-statistics and discrimination indices for CVD risk (delta AUC=+0.053, rIDI=+0.48, NRI=0.42) compared to the clinical predictors alone.
Conclusions: Through a robust metabolomics approach, with independent validation, we have discovered serum orotidine as a novel biomarker of increased odds of CVD in T2D, independent of renal function. Additionally, orotidine may be a biological mediator of the increased CVD risk associated with poor kidney function and may help improve CVD risk prediction in T2D.