Deciphering the Plasma Proteome of Type 2 Diabetes
Mohamed A. Elhadad, Christian Jonasson, Cornelia Huth, Rory Wilson, Christian Gieger, Pamela Matias, Harald Grallert, Johannes Graumann, Valérie Gailus‐Durner, Wolfgang Rathmann, Christine von Toerne, Stefanie M. Hauck, Wolfgang Köenig, Moritz F. Sinner, Tudor I. Oprea, Karsten Suhre, Barbara Thorand, Kristian Hveem, Annette Peters, Mélanie Waldenberger
Abstract
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 >1,000 plasma proteins in the Cooperative Health Research in the Region of Augsburg (KORA) F4 cohort (n = 993, 110 cases), with subsequent replication in the third wave of the Nord-Trøndelag Health Study (HUNT3) 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 bidirectional Mendelian randomization (MR) analysis to prioritize our results. Association analysis of prevalent type 2 diabetes revealed 24 replicated proteins, of which 8 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.