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Circulating protein signatures and causal candidates for type 2 diabetes

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posted on 08.05.2020 by Ada Admin, Valborg Gudmundsdottir, Shaza B Zaghlool, Valur Emilsson, Thor Aspelund, Marjan Ilkov, Elias F Gudmundsson, Stefan M Jonsson, Nuno R Zilhão, John R Lamb, Karsten Suhre, Lori L Jennings, Vilmundur Gudnason
The increasing prevalence of type 2 diabetes poses a major challenge to societies worldwide. Blood-based factors like serum proteins are in contact with every organ in the body to mediate global homeostasis and may thus directly regulate complex processes such as aging and the development of common chronic diseases. We applied a data-driven proteomics approach, measuring serum levels of 4,137 proteins in 5,438 elderly Icelanders and identified 536 proteins associated with prevalent and/or incident type 2 diabetes. We validated a subset of the observed associations in an independent case-control study of type 2 diabetes. These protein associations provide novel biological insights into the molecular mechanisms that are dysregulated prior to and following the onset of type 2 diabetes and can be detected in serum. A bi-directional two-sample Mendelian randomization analysis indicated that serum changes of at least 23 proteins are downstream of the disease or its genetic liability, while 15 proteins were supported as having a causal role in type 2 diabetes.

Funding

The study was funded by the Icelandic Heart Association, National Institute of Aging contracts (N01-AG-12100 and HHSN271201200022C) and Althingi (the Icelandic Parliament). Va.G. is supported by the Icelandic Centre for Research (grant no. 184845-051). Work on the QMDiab cohort was supported by the Biomedical Research Program at Weill Cornell Medicine in Qatar, a program funded by the Qatar Foundation. K.S. is also supported by QNRF grant NPRP11C-0115-180010.

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