Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Sci Rep. 2021 Mar 18;11(1):6197. doi: 10.1038/s41598-021-85684-7.
The number of people affected by Type 2 diabetes mellitus (T2DM) is close to half a billion and is on a sharp rise, representing a major and growing public health burden. Given its mild initial symptoms, T2DM is often diagnosed several years after its onset, leaving half of diabetic individuals undiagnosed. While several classical clinical and genetic biomarkers have been identified, improving early diagnosis by exploring other kinds of omics data remains crucial. In this study, we have combined longitudinal data from two population-based cohorts CoLaus and DESIR (comprising in total 493 incident cases vs. 1360 controls) to identify new or confirm previously implicated metabolomic biomarkers predicting T2DM incidence more than 5 years ahead of clinical diagnosis. Our longitudinal data have shown robust evidence for valine, leucine, carnitine and glutamic acid being predictive of future conversion to T2DM. We confirmed the causality of such association for leucine by 2-sample Mendelian randomisation (MR) based on independent data. Our MR approach further identified new metabolites potentially playing a causal role on T2D, including betaine, lysine and mannose. Interestingly, for valine and leucine a strong reverse causal effect was detected, indicating that the genetic predisposition to T2DM may trigger early changes of these metabolites, which appear well-before any clinical symptoms. In addition, our study revealed a reverse causal effect of metabolites such as glutamic acid and alanine. Collectively, these findings indicate that molecular traits linked to the genetic basis of T2DM may be particularly promising early biomarkers.
受 2 型糖尿病（T2DM）影响的人数接近 5 亿，且呈急剧上升趋势，这是一个重大且日益严重的公共卫生负担。由于 T2DM 的初始症状较轻，通常在发病几年后才被诊断出来，导致一半的糖尿病患者未被诊断出来。虽然已经确定了一些经典的临床和遗传生物标志物，但通过探索其他类型的组学数据来改善早期诊断仍然至关重要。在这项研究中，我们结合了基于人群的 CoLaus 和 DESIR 两个队列的纵向数据（共包括 493 例新发病例与 1360 例对照），以确定新的或确认先前涉及的代谢组学生物标志物，这些标志物可在临床诊断前 5 年以上预测 T2DM 的发病情况。我们的纵向数据为缬氨酸、亮氨酸、肉碱和谷氨酸作为预测未来发生 T2DM 的生物标志物提供了强有力的证据。我们通过基于独立数据的两样本孟德尔随机化（MR）方法，证实了亮氨酸的这种关联的因果关系。我们的 MR 方法还确定了新的代谢物，这些代谢物可能在 T2D 中发挥因果作用，包括甜菜碱、赖氨酸和甘露糖。有趣的是，对于缬氨酸和亮氨酸，检测到了强烈的反向因果效应，这表明 T2DM 的遗传易感性可能导致这些代谢物的早期变化，这些变化出现在任何临床症状之前。此外，我们的研究还揭示了谷氨酸和丙氨酸等代谢物的反向因果效应。总的来说，这些发现表明，与 T2DM 遗传基础相关的分子特征可能是特别有前途的早期生物标志物。
