Protein-metabolite association studies identify novel proteomic determinants of metabolite levels in human plasma.-猫眼课题宝

DOI：

10.1016/j.cmet.2023.07.012

发表时间：

2023-08

期刊：

Cell metabolism

影响因子：

通讯作者：

中科院分区：

生物学1区

文献类型：

作者：

M. Benson;A. Eisman;Usman A. Tahir;Daniel H. Katz;Shuliang Deng;D. Ngo;Jeremy M. Robbins;Alissa Hofmann;Xu Shi;Shuning Zheng;M. Keyes;Zhi Yu;Yan Gao;L. Farrell;Dongxiao Shen;Zsu-Zsu Chen-Zsu;Daniel E Cruz;M. Sims;A. Correa;R. Tracy;P. Durda;K. Taylor;Yongmei Liu;W. Johnson;Xiuqing Guo;J. Yao;Y. Chen;A. Manichaikul;D. Jain;Qiong Yang;C. Bouchard;M. Sarzynski;S. Rich;J. Rotter;Thomas J. Wang;James G. Wilson;C. Clish;I. Sarkar;P. Natarajan;R. Gerszten

虽然已经使用高通量生化图谱鉴定了许多新的基因-代谢物和基因-蛋白质关联，但缺乏利用人类遗传学来阐明循环蛋白质和代谢物之间的因果关系的系统研究。在这里，我们对来自三个人类队列的3626个血浆样本进行了蛋白质-代谢物相关性研究。我们在1,265种蛋白质和365种代谢物之间检测到171,800种显著的蛋白质-代谢物成对相关性，包括代谢和信号通路中已建立的关系，如蛋白质甲状腺激素结合球蛋白和代谢物甲状腺激素，以及数千项新发现。在孟德尔随机化(MR)分析中，我们确定了假定的蛋白质与代谢物之间的因果关系。我们在三种关键蛋白调节基因敲除小鼠的概念验证血浆代谢组学研究中对顶级磁共振相关性进行了实验验证。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认识到的联系。我们提供公开的数据，用于人类新陈代谢和疾病的研究。

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.

Protein-metabolite association studies identify novel proteomic determinants of metabolite levels in human plasma.

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