Revealing the role of the human blood plasma proteome in obesity using genetic drivers

Shaza B. Zaghlool, Sapna Sharma, Megan Molnar, Pamela R. Matías-García, Mohamed A. Elhadad, Melanie Waldenberger, Annette Peters, Wolfgang Rathmann, Johannes Graumann, Christian Gieger, Harald Grallert and Karsten Suhre ()
Additional contact information
Shaza B. Zaghlool: Weill Cornell Medicine-Qatar
Sapna Sharma: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health
Megan Molnar: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health
Pamela R. Matías-García: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health
Mohamed A. Elhadad: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health
Melanie Waldenberger: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health
Annette Peters: Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health
Wolfgang Rathmann: German Center for Diabetes Research (DZD)
Johannes Graumann: Scientific Service Group Biomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, W.G. Kerckhoff Institute
Christian Gieger: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health
Harald Grallert: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health
Karsten Suhre: Weill Cornell Medicine-Qatar

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Blood circulating proteins are confounded readouts of the biological processes that occur in different tissues and organs. Many proteins have been linked to complex disorders and are also under substantial genetic control. Here, we investigate the associations between over 1000 blood circulating proteins and body mass index (BMI) in three studies including over 4600 participants. We show that BMI is associated with widespread changes in the plasma proteome. We observe 152 replicated protein associations with BMI. 24 proteins also associate with a genome-wide polygenic score (GPS) for BMI. These proteins are involved in lipid metabolism and inflammatory pathways impacting clinically relevant pathways of adiposity. Mendelian randomization suggests a bi-directional causal relationship of BMI with LEPR/LEP, IGFBP1, and WFIKKN2, a protein-to-BMI relationship for AGER, DPT, and CTSA, and a BMI-to-protein relationship for another 21 proteins. Combined with animal model and tissue-specific gene expression data, our findings suggest potential therapeutic targets further elucidating the role of these proteins in obesity associated pathologies.

Date: 2021
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DOI: 10.1038/s41467-021-21542-4

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