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

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.
Competing Interests: Declaration of interests M.D.B. reports investigator-initiated grants from Amgen and Boehringer-Ingelheim. P.N. reports investigator-initiated grants from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis and personal fees from Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Novartis, Roche/Genentech; is a co-founder of TenSixteen Bio; is a shareholder of geneXwell, TenSixteen Bio, and Vertex; is a scientific advisory board member of geneXwell and TenSixteen Bio; and reports spousal employment at Vertex, all unrelated to the present work.
(Copyright © 2023. Published by Elsevier Inc.)