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Deciphering the Plasma Proteome of Type 2 Diabetes

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posted on 14.09.2020 by Ada Admin, Mohamed A. Elhadad, Christian Jonasson, Cornelia Huth, Rory Wilson, Christian Gieger, Pamela Matias, Harald Grallert, Johannes Graumann, Valerie Gailus-Durner, Wolfgang Rathmann, Christine von Toerne, Stefanie M. Hauck, Wolfgang Koenig, Moritz F. Sinner, Tudor I Oprea, Karsten Suhre, Barbara Thorand, Kristian Hveem, Annette Peters, Melanie Waldenberger
With an estimated prevalence of 463 million affected, type 2 diabetes represents a major challenge to health care systems worldwide. Analyzing the plasma proteomes of individuals with type 2 diabetes may illuminate hitherto unknown functional mechanisms underlying disease pathology. We assessed the associations between type 2 diabetes and >1000 plasma proteins in the KORA (Cooperative health research in the Region of Augsburg) F4 cohort (n=993, 110 cases), with subsequent replication in the HUNT3 (Third wave of the Nord-Trøndelag Health Study) cohort (n=940, 149 cases). We computed logistic regression models adjusted for age, sex, BMI, smoking status and hypertension. Additionally, we investigated associations with incident type 2 diabetes and performed two-sample bi-directional Mendelian randomization (MR) analysis to prioritize our results. Association analysis of prevalent type 2 diabetes revealed 24 replicated proteins, of which eight are novel. Proteins showing association with incident type 2 diabetes were aminoacylase-1, growth hormone receptor, and insulin-like growth factor binding protein-2. Aminoacylase-1 was associated with both prevalent and incident type 2 diabetes. MR analysis yielded nominally significant causal effects of type 2 diabetes on cathepsin Z and rennin, both known to have roles in the pathophysiological pathways of cardiovascular disease, and of sex hormone-binding globulin on type 2 diabetes. In conclusion, our high-throughput proteomics study replicated previously reported type 2 diabetes-protein associations, and identified new candidate proteins possibly involved in the pathogenesis of type 2 diabetes.

Funding

The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. This work was supported by a grant (WA 4081/1-1) from the German Research Foundation and by the German Federal Ministry of Education and Research (BMBF) within the framework of the EU Joint Programming Initiative ‘A Healthy Diet for a Healthy Life’ (DIMENSION grant number 01EA1902A). This work was further supported by the Biomedical Research Program at Weill Cornell Medicine in Qatar, a program funded by the Qatar Foundation. The HUNT3 study was funded by the Norwegian Ministry of Health, Norwegian University of Science and Technology and Norwegian Research Council, Central Norway Regional Health Authority, the Nord-Trondelag County Council and the Norwegian Institute of Public Health. M.A.E. is supported by the German Center for Cardiovascular Research (DZHK). K.S. is supported by Qatar National Research Fund (QNRF) grant no. NPRPC11-0115-180010. T.I.O. is supported by NIH grants U24 CA224370, U24 TR002278 and U01 CA239108.

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