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 in previous metabolomics studies of CVD. RESEARCH DESIGN AND METHODS We conducted a global serum metabolomics analysis using the Metabolon platform 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 glomerular filtration rate (GFR) (odds ratio [OR] per SD increment 1.94 [95% CI 1.39–2.72], P = 0.0001, and 1.62 [1.26–2.08], P = 0.0001, respectively). Orotidine was also associated with increased odds of CHD in the validation set (OR 1.39 [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 (ΔAUC 0.053, rIDI 0.48, NRI 0.42) compared with 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.

中文翻译：

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血清奥罗替丁：通过代谢组学研究发现的 2 型糖尿病 (T2D) CVD 风险增加的新型生物标志物

目的 通过无假设的全局代谢组学研究，确定 2 型糖尿病 (T2D) 心血管疾病 (CVD) 风险的新生物标志物，同时考虑肾功能，肾功能是之前 CVD 代谢组学研究中经常被忽视的一个重要混杂因素。研究设计和方法 我们使用 Metabolon 平台在 Joslin 肾脏研究的发现集中进行了全球血清代谢组学分析，该研究采用嵌套病例对照设计，包括 409 名 T2D 患者。应用逻辑回归来评估 CVD 事件与 Metabolon 平台检测到的 671 种代谢物中的每一种（在肾功能和其他 CVD 危险因素调整前后）之间的关联。在 Joslin 心脏研究的验证集中对重要代谢物进行了绝对定量分析，该验证集包括 599 名患有或不患有严重冠心病 (CHD) 临床证据的 T2D 患者。结果 在发现组中，调整肾小球滤过率 (GFR) 后，血清乳清苷和 2-哌啶酮与 CVD 发生几率增加显着相关（比值比 [OR] 每 SD 增量 1.94 [95% CI 1.39–2.72]，P = 0.0001 和 1.62 [1.26–2.08]，P = 0.0001，分别）。在验证集中，奥罗替丁也与 CHD 几率增加相关（OR 1.39 [1.11–1.75]），而 2-哌啶酮则没有重复。此外，乳清苷与 GFR 呈负相关，肾功能下降对 CVD 风险的影响有 60% 是由乳清苷介导的。与单独的临床预测因子相比，在已建立的临床预测因子中添加乳清苷可改善 (P < 0.05) CVD 风险的 C 统计和辨别指数 (ΔAUC 0.053、rIDI 0.48、NRI 0.42)。结论 通过可靠的代谢组学方法和独立验证，我们发现血清乳清苷可以作为 T2D 中 CVD 几率增加的新型生物标志物，且与肾功能无关。此外，乳清苷可能是与肾功能不良相关的 CVD 风险增加的生物介质，并可能有助于改善 T2D 的 CVD 风险预测。