title: 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.
abstract: 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.
authors.affiliation: Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany. georg.homuth@uni-greifswald.de.
authors.forename: Georg
authors.initials: G
authors.lastname: Homuth
authors.affiliation: Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. simone.wahl@helmholtz-muenchen.de.|German Center for Diabetes Research (DZD), Neuherberg, Germany. simone.wahl@helmholtz-muenchen.de.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. simone.wahl@helmholtz-muenchen.de.
authors.forename: Simone
authors.initials: S
authors.lastname: Wahl
authors.affiliation: Klinik für Allgemeine und Interventionelle Kardiologie, Universitäres Herzzentrum Hamburg, Hamburg, Germany. christian_m@gmx.net.|DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany. christian_m@gmx.net.
authors.forename: Christian
authors.initials: C
authors.lastname: Müller
authors.affiliation: Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany. claudia.schurmann@mssm.edu.|DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany. claudia.schurmann@mssm.edu.|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. claudia.schurmann@mssm.edu.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schurmann
authors.affiliation: Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany. ulrike.maeder@uni-greifswald.de.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Mäder
authors.affiliation: Klinik für Allgemeine und Interventionelle Kardiologie, Universitäres Herzzentrum Hamburg, Hamburg, Germany. s.blankenberg@uke.de.|DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany. s.blankenberg@uke.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Blankenberg
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany. maren.carstensen@ddz.uni-duesseldorf.de.|German Center for Diabetes Research (DZD e.V.), partner site Düsseldorf, Düsseldorf, Germany. maren.carstensen@ddz.uni-duesseldorf.de.
authors.forename: Maren
authors.initials: M
authors.lastname: Carstensen
authors.affiliation: DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany. mdoerr@uni-greifswald.de.|Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany. mdoerr@uni-greifswald.de.
authors.forename: Marcus
authors.initials: M
authors.lastname: Dörr
authors.affiliation: Institute of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany. karlhans.endlich@uni-greifswald.de.
authors.forename: Karlhans
authors.initials: K
authors.lastname: Endlich
authors.affiliation: German Center for Diabetes Research (DZD), Neuherberg, Germany. che74@gmx.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Englbrecht
authors.affiliation: DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany. felix@uni-greifswald.de.|Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany. felix@uni-greifswald.de.
authors.forename: Stephan B
authors.initials: SB
authors.lastname: Felix
authors.affiliation: Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. christian.gieger@helmholtz-muenchen.de.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. christian.gieger@helmholtz-muenchen.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. harald.grallert@helmholtz-muenchen.de.|German Center for Diabetes Research (DZD), Neuherberg, Germany. harald.grallert@helmholtz-muenchen.de.
authors.forename: Harald
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authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany. Christian.Herder@ddz.uni-duesseldorf.de.|German Center for Diabetes Research (DZD e.V.), partner site Düsseldorf, Düsseldorf, Germany. Christian.Herder@ddz.uni-duesseldorf.de.
authors.forename: Christian
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authors.affiliation: Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. Illig.Thomas@mh-hannover.de.|Hannover Unified Biobank, Hannover Medical School, Hannover, Germany. Illig.Thomas@mh-hannover.de.|Institute for Human Genetics, Hannover Medical School, Hannover, Germany. Illig.Thomas@mh-hannover.de.
authors.forename: Thomas
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authors.affiliation: DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany. Jochen.Kruppa@med.uni-goettingen.de.|Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany. Jochen.Kruppa@med.uni-goettingen.de.
authors.forename: Jochen
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authors.lastname: Kruppa
authors.affiliation: Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. carola.marzi@helmholtz-muenchen.de.|German Center for Diabetes Research (DZD), Neuherberg, Germany. carola.marzi@helmholtz-muenchen.de.
authors.forename: Carola S
authors.initials: CS
authors.lastname: Marzi
authors.affiliation: Department of Internal Medicine A, University Medicine Greifswald, Greifswald, Germany. mayerle@uni-greifswald.de.
authors.forename: Julia
authors.initials: J
authors.lastname: Mayerle
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. Meitinger@helmholtz-muenchen.de.|DZHK (German Centre for Cardiovascular Research), partner site Munich, Munich, Germany. Meitinger@helmholtz-muenchen.de.|Institut für Humangenetik, Technische Universität München, München, Germany. Meitinger@helmholtz-muenchen.de.|Munich Heart Alliance, Munich, Germany. Meitinger@helmholtz-muenchen.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu, Estonia. andres.metspalu@ut.ee.
authors.forename: Andres
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authors.lastname: Metspalu
authors.affiliation: DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany. matthias.nauck@uni-greifswald.de.|Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany. matthias.nauck@uni-greifswald.de.
authors.forename: Matthias
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authors.lastname: Nauck
authors.affiliation: Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. peters@helmholtz-muenchen.de.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. peters@helmholtz-muenchen.de.|Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. peters@helmholtz-muenchen.de.|Institut für Humangenetik, Technische Universität München, München, Germany. peters@helmholtz-muenchen.de.
authors.forename: Annette
authors.initials: A
authors.lastname: Peters
authors.affiliation: Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, University Düsseldorf, Düsseldorf, Germany. rathmann@ddz.uni-duesseldorf.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rathmann
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu, Estonia. eva.reinmaa@ut.ee.|Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia. eva.reinmaa@ut.ee.
authors.forename: Eva
authors.initials: E
authors.lastname: Reinmaa
authors.affiliation: Institute of Physiology, University Medicine Greifswald, Karlsburg, Germany. rettig@uni-greifswald.de.
authors.forename: Rainer
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authors.lastname: Rettig
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany. Michael.Roden@ddz.uni-duesseldorf.de.|German Center for Diabetes Research (DZD e.V.), partner site Düsseldorf, Düsseldorf, Germany. Michael.Roden@ddz.uni-duesseldorf.de.|Division of Endocrinology and Diabetology, University Hospital Düsseldorf, Düsseldorf, Germany. Michael.Roden@ddz.uni-duesseldorf.de.
authors.forename: Michael
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authors.lastname: Roden
authors.affiliation: DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany. arne.schillert@imbs.uni-luebeck.de.|Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany. arne.schillert@imbs.uni-luebeck.de.
authors.forename: Arne
authors.initials: A
authors.lastname: Schillert
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. katharina.schramm@helmholtz-muenchen.de.
authors.forename: Katharina
authors.initials: K
authors.lastname: Schramm
authors.affiliation: Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany. steil@uni-greifswald.de.
authors.forename: Leif
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authors.lastname: Steil
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. strauch@helmholtz-muenchen.de.|Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany. strauch@helmholtz-muenchen.de.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Strauch
authors.affiliation: Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany. ateumer@uni-greifswald.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Teumer
authors.affiliation: DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany. voelzke@uni-greifswald.de.|Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany. voelzke@uni-greifswald.de.
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.affiliation: DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany. henri.wallaschofski@hotmail.com.|Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany. henri.wallaschofski@hotmail.com.
authors.forename: Henri
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authors.affiliation: Preventive Cardiology and Preventive Medicine, Department of Medicine 2, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany. philipp.wild@unimedizin-mainz.de.|Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany. philipp.wild@unimedizin-mainz.de.|DZHK (German Centre for Cardiovascular Research), partner site Rhine-Main, Mainz, Germany. philipp.wild@unimedizin-mainz.de.
authors.forename: Philipp S
authors.initials: PS
authors.lastname: Wild
authors.affiliation: Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany. ziegler@imbs.uni-luebeck.de.|Zentrum für Klinische Studien, Universität zu Lübeck, Lübeck, Germany. ziegler@imbs.uni-luebeck.de.|School of Statistics, Mathematics and Computer Science, University of KwaZulu-Natal, Pietermaritzburg, South Africa. ziegler@imbs.uni-luebeck.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ziegler
authors.affiliation: Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany. voelker@uni-greifswald.de.|DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany. voelker@uni-greifswald.de.
authors.forename: Uwe
authors.initials: U
authors.lastname: Völker
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. Prokisch@helmholtz-muenchen.de.|DZHK (German Centre for Cardiovascular Research), partner site Munich, Munich, Germany. Prokisch@helmholtz-muenchen.de.|Institut für Humangenetik, Technische Universität München, München, Germany. Prokisch@helmholtz-muenchen.de.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Klinik für Allgemeine und Interventionelle Kardiologie, Universitäres Herzzentrum Hamburg, Hamburg, Germany. t.zeller@uke.de.|DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany. t.zeller@uke.de.
authors.forename: Tanja
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authors.lastname: Zeller
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001769:Blood / Q000378:metabolism*; D015992:Body Mass Index; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D012156:Reticulocytes / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D007328:Insulin; D012333:RNA, Messenger; D017382:Reactive Oxygen Species