Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA; Center for Biomedical Informatics, Brown University, Providence, RI, USA.
Cell Metab. 2023 Sep 5;35(9):1646-1660.e3. doi: 10.1016/j.cmet.2023.07.012. Epub 2023 Aug 14.
Although many novel gene-metabolite and gene-protein associations have been identified using high-throughput biochemical profiling, systematic studies that leverage human genetics to illuminate causal relationships between circulating proteins and metabolites are lacking. Here, we performed protein-metabolite association studies in 3,626 plasma samples from three human cohorts. We detected 171,800 significant protein-metabolite pairwise correlations between 1,265 proteins and 365 metabolites, including established relationships in metabolic and signaling pathways such as the protein thyroxine-binding globulin and the metabolite thyroxine, as well as thousands of new findings. In Mendelian randomization (MR) analyses, we identified putative causal protein-to-metabolite associations. We experimentally validated top MR associations in proof-of-concept plasma metabolomics studies in three murine knockout strains of key protein regulators. These analyses identified previously unrecognized associations between bioactive proteins and metabolites in human plasma. We provide publicly available data to be leveraged for studies in human metabolism and disease.
尽管使用高通量生化分析已经鉴定出许多新的基因-代谢物和基因-蛋白质关联，但利用人类遗传学阐明循环蛋白和代谢物之间因果关系的系统研究仍然缺乏。在这里，我们在来自三个人类队列的 3626 个血浆样本中进行了蛋白质-代谢物关联研究。我们在 1265 种蛋白质和 365 种代谢物之间检测到了 171800 个显著的蛋白质-代谢物成对相关性，包括代谢和信号通路中的已建立关系，如甲状腺素结合球蛋白和甲状腺素等代谢物，以及数千个新发现。在孟德尔随机化（MR）分析中，我们确定了潜在的因果蛋白-代谢物关联。我们在三个关键蛋白调节剂的小鼠敲除品系的概念验证血浆代谢组学研究中对顶级 MR 关联进行了实验验证。这些分析确定了人类血浆中生物活性蛋白和代谢物之间以前未被识别的关联。我们提供了公开可用的数据，可用于人类代谢和疾病的研究。
