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

BMC Medical Genomics

Tanja Zeller^1,16  Holger Prokisch³  Uwe Völker⁵  Andreas Ziegler^1,11  Philipp S. Wild²  Henri Wallaschofski⁵  Henry Völzke⁵  Alexander Teumer⁷  Konstantin Strauch^1,12  Leif Steil⁷  Katharina Schramm^1,17  Arne Schillert^1,16  Michael Roden^1,19  Rainer Rettig^1,13  Eva Reinmaa^1,14  Wolfgang Rathmann⁴  Annette Peters^1,15  Matthias Nauck⁵  Andres Metspalu⁹  Thomas Meitinger^2,20  Julia Mayerle⁸  Carola S. Marzi⁶  Jochen Kruppa^1,16  Thomas Illig¹  Christian Herder^1,19  Harald Grallert⁶  Christian Gieger^1,15  Stephan B. Felix⁵  Christian Englbrecht⁶  Karlhans Endlich^1,10  Marcus Dörr⁵  Maren Carstensen^1,19  Stefan Blankenberg^1,16  Ulrike Mäder⁷  Claudia Schurmann^1,18  Christian Müller^1,16  Simone Wahl^1,15  Georg Homuth⁷ 

[1] Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany;DZHK (German Centre for Cardiovascular Research), partner site Rhine-Main, Mainz, Germany;Institut für Humangenetik, Technische Universität München, München, Germany;Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, University Düsseldorf, Düsseldorf, Germany;DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany;German Center for Diabetes Research (DZD), Neuherberg, Germany;Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany;Department of Internal Medicine A, University Medicine Greifswald, Greifswald, Germany;Estonian Genome Center, University of Tartu, Tartu, Estonia;Institute of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany;School of Statistics, Mathematics and Computer Science, University of KwaZulu-Natal, Pietermaritzburg, South Africa;Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany;Institute of Physiology, University Medicine Greifswald, Karlsburg, Germany;Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia;Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany;DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany;Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany;Present Address: The Charles Bronfman Institute for Personalized Medicine, Genetics of Obesity & Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, USA;Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany;Munich Heart Alliance, Munich, Germany

关键词: Insulin signaling;    Oxidative stress;    Type 2 diabetes;    Insulin resistance;    Obesity;    BMI;    Transcriptome-wide association study (TWAS);    Transcriptomics;   

Others  :  1228947
DOI  :  10.1186/s12920-015-0141-x

 received in 2015-04-02, accepted in 2015-10-05,  发布年份 2015

【 摘 要 】

Background

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.

Methods

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.

Results

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).

Conclusions

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.

【 授权许可】

   
2015 Homuth et al.

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