Extensive alterations of the whole-blood transcriptome are associated with body mass index: results of an mRNA profiling study involving two large population-based cohorts

Georg Homuth, Simone Wahl, Christian Müller, Claudia Schurmann, Ulrike Mäder, Stefan Blankenberg, Maren Carstensen, Marcus Dörr, Karlhans Endlich, Christian Englbrecht, Stephan B. Felix, Christian Gieger, Harald Grallert, Christian Herder, Thomas Illig, Jochen Kruppa, Carola S. Marzi, Julia Mayerle, Thomas Meitinger, Andres Metspalu, Matthias Nauck, Annette Peters, Wolfgang Rathmann, Eva Reinmaa, Rainer Rettig, Michael Roden, Arne Schillert, Katharina Schramm, Leif Steil, Konstantin Strauch, Alexander Teumer, Henry Völzke, Henri Wallaschofski, Philipp S. Wild, Andreas Ziegler, Uwe Völker, Holger Prokisch, Tanja Zeller

Obesity, defined as pathologically increased body mass index (BMI), is strongly related to an increased risk for numerous common cardiovascular and metabolic diseases. It is particularly associated with insulin resistance, hyperglycemia, and systemic oxidative stress and represents the most important risk factor for type 2 diabetes (T2D). However, the pathophysiological mechanisms underlying these associations are still not completely understood. Therefore, in order to identify potentially disease-relevant BMI-associated gene expression signatures, a transcriptome-wide association study (TWAS) on BMI was performed. Whole-blood mRNA levels determined by array-based transcriptional profiling were correlated with BMI in two large independent population-based cohort studies (KORA F4 and SHIP-TREND) comprising a total of 1977 individuals. Extensive alterations of the whole-blood transcriptome were associated with BMI: More than 3500 transcripts exhibited significant positive or negative BMI-correlation. Three major whole-blood gene expression signatures associated with increased BMI were identified. The three signatures suggested: i) a ratio shift from mature erythrocytes towards reticulocytes, ii) decreased expression of several genes essentially involved in the transmission and amplification of the insulin signal, and iii) reduced expression of several key genes involved in the defence against reactive oxygen species (ROS). Whereas the first signature confirms published results, the other two provide possible mechanistic explanations for well-known epidemiological findings under conditions of increased BMI, namely attenuated insulin signaling and increased oxidative stress. The putatively causative BMI-dependent down-regulation of the expression of numerous genes on the mRNA level represents a novel finding. BMI-associated negative transcriptional regulation of insulin signaling and oxidative stress management provide new insights into the pathogenesis of metabolic syndrome and T2D.